Fused pyrimidine compound or salt thereof

ABSTRACT

wherein A, R1 to R3, X, and n are as defined in the specification.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

The present application is a divisional of U.S. Ser. No. 15/700,800filed Sep. 11, 2017, which is a continuation of PCT/JP2016/076354, filedSep. 7, 2016, which claims priority to Japanese Patent Application No.2015-177073 filed on Sep. 8, 2015, which are incorporated by referencein their entirety.

TECHNICAL FIELD

The present invention relates to a novel fused pyrimidine compoundhaving RET inhibitory activity or a salt thereof, and to apharmaceutical composition containing the compound or salt.

BACKGROUND ART

Various protein kinases are present in vivo and are known to be involvedin a wide range of functional regulations. RET is a receptor tyrosinekinase identified as one of the proto-oncogenes. RET binds to the glialcell line-derived neurotrophic factor (GDNF) and GDNF receptor to form acomplex, which enables RET to perform physiological functions throughintracellular phosphorylation signaling (Non-patent Literature 1). Astudy reports that in normal tissues, RET contributes to kidneydevelopment and neurogenesis during fetal life (Non-patent Literature2). Some studies indicate that in cancers, such as lung cancer, thyroidcancer, breast cancer, pancreas cancer, and prostate cancer, thetranslocation, mutation, or overexpression of the RET gene enhances itsactivation to thereby contribute to cell growth, tumor formation, ortissue infiltration (Non-patent Literature 3, 4, 5, 6, 7, and 8). Inaddition, RET is known to be an adverse prognostic factor of cancer, asindicated in some reports that the translocation of RET and its enhancedactivation level are also inversely correlated with prognosis in cancer(Non-patent Literature 9, 10, 11, and 12).

Therefore, an inhibitor capable of inhibiting RET activity is thought tobe useful as a therapeutic agent for diseases associated with abnormallyenhanced RET signaling pathways.

It is expected, for example, that in cancers involving translocated,mutated, and overexpressed RET genes, the administration of a medicamentcapable of specifically inhibiting RET will selectively and intensivelysuppress the proliferation of cancer cells and contribute to thetreatment, life prolongation, and improvement in quality of life ofcancer patients.

As an example of such compounds having RET inhibitory activity, PP1 isknown (Non-patent Literature 13). PP1 is known to exhibit highinhibitory activity against not only RET but also SRC (Non-patentLiterature 14), c-Kit, Bcr-Abl (Non-patent Literature 15 and 16), andothers. For example, as side effects, the inhibition of SRC may lead toabnormally enhanced bone formation, and the inhibition of LCK maysuppress T cells (Non-patent Literature 17 and 18). Since multikinaseinhibitors inhibit not only RET but also various signaling pathways,inhibiting cell growth and other functions, the inhibitors raiseconcerns about possible various side effects, which may require dosereduction or drug holidays, thus leading to insufficient RET inhibitoryactivity. From the standpoint of side effect reduction, there has been ademand for a RET inhibitor having high inhibitory activity against RETwhile exhibiting low inhibitory activity against other kinases.

CITATION LIST Patent Literature

-   Patent Literature 1: U.S. Pat. No. 5,665,721-   Patent Literature 2: WO96/40686A1

Non-Patent Literature

-   Non-patent Literature 1: Lois M. Mulligan, Nature Rev., 14(3): pp.    173-186, (2014)-   Non-patent Literature 2: Carlos F. Ibanez, Cold Spring Harb Perspect    Biol., 5(2): pp. 1-10, (2013)-   Non-patent Literature 3: Takashi Kohno, Nature Med., 18(3): pp.    375-377, (2012)-   Non-patent Literature 4: Massimo Santoro, Eur J Endocrinol., 155:    pp. 645-653, (2006)-   Non-patent Literature 5: Marjan Zarif Yeganeh, Asian Pac J Cancer    Prev., 16(6): pp. 2107-2117, (2015)-   Non-patent Literature 6: Albana Gattelli, EMBO Mol Med., 5: pp.    1335-1350, (2013)-   Non-patent Literature 7: Yoshinori Ito, Surgery, 138: pp. 788-794,    (2005)-   Non-patent Literature 8: Dawn M. Dawson, J Natl Cancer Inst., 90(7):    pp. 519-523, (1998)-   Non-patent Literature 9: Weijing Cai, Cancer, 119: pp. 1486-1494,    (2013)-   Non-patent Literature 10: Rossella Elisei, J Clin Endocrinol Metab.,    93(3): pp. 682-687, (2008)-   Non-patent Literature 11: Albana Gattelli, EMBO Mol Med., 5: pp.    1335-1350, (2013)-   Non-patent Literature 12: Q Zeng, J. Int. Med. Res., 36: pp.    656-664, (2008)-   Non-patent Literature 13: Francesca Carlomagno, Cancer Res., 62(4):    pp. 1077-1082, (2002)-   Non-patent Literature 14: Johannes Waltenberger, Circ Res., 85(1):    pp. 12-22, (1999)-   Non-patent Literature 15: Louise Tatton, J Biol Chem., 278(7): pp.    4847-4853, (2003)-   Non-patent Literature 16: Markus Warmuth, Blood. 101(2): pp.    664-672, (2003)-   Non-patent Literature 17: Carolyn Lowe, Proc Natl Acad Sci USA,    90(10): pp. 4485-4489, (1993)-   Non-patent Literature 18: Thierry Molina, Nature, 357(6374): pp.    161-164, (1992)

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a novel RET inhibitorcomprising, as an active ingredient, a compound or a salt thereof thathave not been known for their RET inhibitory activity, and to alsoprovide an agent for preventing or treating diseases (e.g., malignanttumors) that can be prevented or treated by RET inhibitory activity.Another object of the present invention is to provide a novel compoundor a salt thereof that selectively and potently inhibit RET.

Solution to Problem

The present inventors conducted extensive research to achieve the aboveobjects, and consequently found that a compound group represented byFormulas (I) and (I′) below showed excellent inhibitory activity againstRET and kinase selectivity, and was useful as a pharmaceuticalpreparation for treating RET-related diseases, such as malignant tumors.Thus, the present invention has been completed.

Specifically, the present invention provides a compound represented byFormula (I) below or a salt thereof:

wherein A is pyrazolyl substituted with n-number of R¹;R¹ ishalogen,cyano,substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;R² issubstituted or unsubstituted C1-C10 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C2-C6 alkenyl,substituted or unsubstituted C3-C7 cycloalkenyl,substituted or unsubstituted C4-C12 bridged cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;X isN orCR³, wherein R³ is

hydrogen,

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkenyl,

substituted or unsubstituted C2-C6 alkynyl,

substituted or unsubstituted C1-C6 alkoxy,

substituted or unsubstituted amino,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclicunsaturated heterocyclic group containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and

n is an integer of 0 to 3,

wherein when n is 2 or 3, R¹ may be identical or different from eachother.

The present invention also provides a compound represented by Formula(I′) below or a salt thereof:

wherein A is pyrazolyl substituted with n-number of R¹;R¹ ishalogen,cyano,substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;R² issubstituted or unsubstituted C1-C10 alkyl,substituted or unsubstituted C3-C4 cycloalkyl,substituted or unsubstituted C2-C6 alkenyl,substituted or unsubstituted C3-C4 cycloalkenyl,substituted or unsubstituted C4-C12 bridged cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;X isN orCR³, wherein R³ is

hydrogen,

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkenyl,

substituted or unsubstituted C2-C6 alkynyl,

substituted or unsubstituted C1-C6 alkoxy,

substituted or unsubstituted amino,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclicunsaturated heterocyclic group containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and

n is an integer of 0 to 3,

wherein when n is 2 or 3, R¹ may be identical or different from eachother.

The present invention also provides a RET inhibitor comprising acompound represented by Formula (I) or (I′) above or a salt thereof asan active ingredient.

The present invention also provides a pharmaceutical compositioncomprising a compound represented by Formula (I) or (I′) above or a saltthereof.

The present invention also provides a pharmaceutical compositioncomprising a compound represented by Formula (I) or (I′) above or a saltthereof, wherein the pharmaceutical composition prevents or treats adisease that can be treated by RET inhibition.

The present invention also provides an antitumor agent comprising acompound represented by Formula (I) or (I′) above or a salt thereof.

The present invention also provides an antitumor agent comprising acompound represented by Formula (I) or (I′) above or a salt thereof,wherein the antitumor agent treats a malignant tumor with enhancedactivation of RET.

The present invention also provides a compound represented by Formula(I) or (I′) above or a salt thereof for use in prevention or treatmentof a malignant tumor.

The present invention also provides a compound represented by Formula(I) or (I′) above or a salt thereof for use in prevention or treatmentof a malignant tumor, wherein the malignant tumor is a malignant tumorwith enhanced activation of RET.

The present invention also provides use of a compound represented byFormula (I) or (I′) above or a salt thereof for producing an antitumoragent.

The present invention also provides use of a compound represented byFormula (I) or (I′) above or a salt thereof for producing an antitumoragent, wherein the antitumor agent is an antitumor agent for treating amalignant tumor with enhanced activation of RET.

The present invention also provides use of a compound represented byFormula (I) or (I′) above or a salt thereof for producing a RETinhibitor.

The present invention also provides a method for preventing or treatinga malignant tumor, comprising administering a compound represented byFormula (I) or (I′) above or a salt thereof to a mammal.

The present invention also provides a method for preventing or treatinga malignant tumor, comprising administering a compound represented byFormula (I) or (I′) above or a salt thereof to a mammal, wherein themalignant tumor is a malignant tumor with enhanced activation of RET.

The present invention also provides a method of inhibiting RETcomprising administering a compound represented by Formula (I) or (I′)above or a salt thereof to a mammal.

Patent Literature 1 and 2 do not suggest RET inhibitory activity orantitumor effects.

PP1 mentioned above is known as a compound having RET inhibitoryactivity. In PP1, a p-toluyl group is bonded to a fused ring pyrimidineskeleton; however, its structure is significantly different from thepresent invention in that PP1 does not have a pyrazolyl group continuouswith an amide bond, which is the feature of the compound of the presentinvention. Moreover, as shown in Test Examples provided later, thecompound or a salt thereof of the present invention has thecharacteristic of a high RET selectivity, which is different from PP1.

Advantageous Effects of Invention

The present invention can provide a novel RET inhibitor and an agent forpreventing or treating diseases (e.g., malignant tumors) that can beprevented or treated by RET inhibitory activity, by using, as theiractive ingredients, compounds represented by Formulas (I) and (I′) orsalts thereof, which have not been known for their RET inhibitoryactivity. In particular, a novel compound represented by Formula (I′) ora salt thereof, etc., are preferred.

It was revealed that the compound or a salt thereof of the presentinvention has excellent RET-selective inhibitory activity and a cancercell growth inhibitory effect.

RET is known as an oncogene and known to be activated by thetranslocation, mutation, or overexpression of the RET gene in many typesof cancer (Non-patent Literature 3, 4, 5, 6, 7, and 8). Thus, thecompound or a salt thereof of the present invention, both of which havea high RET inhibitory activity, is useful as an agent for preventingand/or treating cancer.

Further, the compound or a salt thereof of the present inventionselectively and potently inhibits RET, rather than other kinases, suchas SRC and LCK; therefore, side effects can be reduced, and improvementin safety can be expected.

Moreover, the compound or a salt thereof of the present invention isadvantageous in that it has excellent stability in hepatic microsomes,excellent exposure in the blood can be expected, and there is no concernabout Cyp inhibition.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates changes in relative tumor volume during the test inTest Example 5.

FIG. 2 illustrates changes in relative tumor volume during the test inTest Example 5

FIG. 3 illustrates changes in body weight during the test in TestExample 5.

FIG. 4 illustrates changes in body weight during the test in TestExample 5.

DESCRIPTION OF EMBODIMENTS

The compounds of the present invention represented by Formulas (I) and(I′) above are compounds having a fused ring pyrimidine skeleton with apyrazolyl group via an amide bond, and they have not been known fortheir RET inhibitory activity. In particular, the compound representedby Formula (I′) above or a salt thereof, etc., are novel compounds thatare not disclosed in any of the above prior art documents.

In the present invention, the compounds represented by Formulas (I) and(I′) are also referred to simply as “Compound (I)” and “Compound (I′),”respectively.

In the present specification, unless otherwise specified, examples ofthe “substituent” include halogen, hydroxy, cyano, nitro, alkyl,halogenoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl,bridged cycloalkyl, aralkyl, alkenyl, alkynyl, alkoxy, halogenoalkoxy,cycloalkoxy, cycloalkyl-alkoxy, aralkyloxy, alkylthio,cycloalkyl-alkylthio, amino, mono- or dialkylamino,cycloalkyl-alkylamino, acyl, acyloxy, oxo, carboxyl, alkoxycarbonyl,aralkyloxycarbonyl, carbamoyl, saturated or unsaturated heterocyclicgroup, aromatic hydrocarbon, saturated heterocyclic oxy, etc. (Thesesubstituents are also referred to as “Substituents B.”) When asubstituent listed above is present, the number thereof is typicallyone, two, or three.

In the present specification, examples of the “halogen” includefluorine, chlorine, bromine, and iodine.

In the present specification, the “alkyl” may be linear or branched.Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, n-hexyl,1,1-dimethylpropyl, 1,1,2,2-tetramethylethyl, n-heptyl,1,1,2,2-tetramethylpropyl, n-octyl, n-nonyl, n-decyl, etc.; andspecifically include C1-C10 alkyl, C1-C6 alkyl, etc.

In the present specification, examples of the “halogenoalkyl” includeC1-C10 linear or branched alkyl having one or more (e.g., 1 to 10, 1 to7, or 1 to 5) halogen atoms (halogeno C1-C10 alkyl). Examples includefluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl,fluoroethyl, 1,1,1-trifluoroethyl, monofluoro-n-propyl,perfluoro-n-propyl, perfluoroisopropyl, monofluoro-n-butyl,monofluoro-n-pentyl, monofluoro-n-hexyl, etc.; and specifically includehalogeno C1-C6 alkyl, halogeno C1-C4 alkyl, etc.

In the present specification, examples of the “hydroxyalkyl” includeC1-C10 linear or branched alkyl having one or more (e.g., 1 to 5, 1 to3, or 1) hydroxy groups (hydroxy C1-C10 alkyl). Examples includehydroxymethyl, hydroxyethyl (1-hydroxyethyl or 2-hydroxyethyl),hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, etc.; andspecifically include hydroxy C1-C6 alkyl, hydroxy C1-C4 alkyl, etc.

In the present specification, examples of the “alkoxyalkyl” includealkoxyalkyl in which the alkoxy moiety is C1-C6 linear or branchedalkoxy, and the alkyl moiety is C1-C10 linear or branched alkyl (C1-C6alkoxy C1-C10 alkyl). Examples of C1-C6 linear or branched alkoxyinclude those in which the alkyl moiety is C1-C6 alkoxy among theexamples of the alkyl mentioned above. Examples of the alkoxyalkylinclude methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl,2-methoxyethyl, 1-methoxy-n-propyl, 3-methoxy-n-propyl,2-ethoxy-n-butyl, 4-methoxy-n-butyl, 5-methoxy-n-pentyl,6-methoxy-n-hexyl, etc.; and specifically include C1-C4 alkoxy C1-C6alkyl, C1-C4 alkoxy C1-C4 alkyl, etc.

In the present specification, specific examples of the “cycloalkyl”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc.; and specifically include C3-C7 cycloalkyl, C3-C5 cycloalkyl, C3-C4cycloalkyl, etc. In the present invention, the “cycloalkyl” should bespecified independently from “bridged cycloalkyl,” described later.Therefore, in the present invention, the “bridged cycloalkyl” isexcluded from the “cycloalkyl”.

In the present specification, examples of the “cycloalkyl-alkyl” includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, etc.; and specifically includeC3-C7 cycloalkyl-substituted C1-C10 alkyl, C3-C5 cycloalkyl-substitutedC1-C6 alkyl, etc.

In the present specification, the “bridged cycloalkyl” refers to bridgedcyclic hydrocarbon in which the carbocyclic ring constituting thebridged cyclic hydrocarbon has a saturated structure. In the presentspecification, examples of the “bridged cycloalkyl” includebicyclo[1.1.0]butyl (bicyclo[1.1.0]butan-1-yl orbicyclo[1.1.0]butan-2-yl), bicyclo[1.1.1]pentyl(bicyclo[1.1.1]pentan-1-yl or bicyclo[1.1.1]pentan-2-yl),bicyclo[3.1.0]hexyl (bicyclo[3.1.0]hexan-1-yl, bicyclo[3.1.0]hexan-2-yl,bicyclo[3.1.0]hexan-3-yl, or bicyclo[3.1.0]hexan-6-yl),bicyclo[2.2.1]heptyl (bicyclo[2.2.1]heptan-1-yl,bicyclo[2.2.1]heptan-2-yl, or bicyclo[2.2.1]heptan-7-yl),bicyclo[3.1.1]heptyl (bicyclo[3.1.1]heptan-1-yl,bicyclo[3.1.1]heptan-2-yl, bicyclo[3.1.1]heptan-3-yl, orbicyclo[3.1.1]heptan-6-yl), adamanthyl (adamantan-1-yl oradamantan-2-yl), etc.; and specifically include C4-C12 bridgedcycloalkyl, etc.

In the present specification, examples of the “aralkyl” include benzyl,phenethyl, naphthylmethyl, fluorenylmethyl, etc.; and specificallyinclude C7-C14 aralkyl, etc.

In the present specification, the “alkenyl” may be linear or branched,and refers to unsaturated aliphatic hydrocarbon having at least one(e.g., 1 or 2, or 1) double bond. Examples include vinyl, allyl,1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-,3-, or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl,1-cyclopentenyl, 1-cyclohexenyl, 3-methyl-3-butenyl, etc.; andspecifically include C2-C6 alkenyl, C2-C4 alkenyl, etc.

In the present specification, the “cycloalkenyl” refers to unsaturatedalicyclic hydrocarbon having at least one (e.g., 1 or 2, or 1) doublebond. Examples include cyclopropenyl (e.g., 2-cyclopropen-1-yl),cyclobutenyl (e.g., 2-cyclobuten-1-yl), cyclopentenyl (e.g.,2-cyclopenten-1-yl and 3-cyclopenten-1-yl), cyclopentadienyl (e.g.,2,4-cyclopentadien-1-yl), cyclohexenyl (e.g., 3-cyclohexen-1-yl),cycloheptenyl (e.g., 3-cyclohepten-1-yl), etc.; and specifically includeC3-C7 cycloalkenyl, C3-C5 cycloalkenyl, C3-C4 cycloalkenyl, etc.

In the present specification, the “alkynyl” may be linear, branched, orcyclic, and refers to unsaturated hydrocarbon having at least one triplebond. Examples include ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butynyl,1-methyl-2-propynyl, etc.; and specifically include C2-C6 alkynyl, C2-C4alkynyl, etc.

In the present specification, the “alkoxy” may be linear or branched.Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, etc.; andspecifically include C1-C6 alkoxy, C1-C4 alkoxy, etc.

In the present specification, the “halogenoalkoxy” refers to C1-C6linear or branched alkoxy having one or more (e.g., 1 to 10, 1 to 7, or1 to 5) halogen atoms (halogeno C1-C6 alkoxy). Examples includefluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy,fluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy,perfluoro-n-propoxy, perfluoro-isopropoxy, etc.; and specificallyinclude halogeno C1-C6 alkoxy, halogeno C1-C4 alkoxy, etc.

In the present specification, specific examples of the “cycloalkoxy”include cyclopropoxy, cyclobutoxy, cyclopenthyloxy, cyclohexyloxy,cycloheptyloxy, etc.; and specifically include C3-C7 cycloalkoxy.

In the present specification, examples of the “cycloalkyl-alkoxy”include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclohexylmethoxy, cycloheptylmethoxy, etc.; and specifically includeC3-C7 cycloalkyl-substituted C1-C4 alkoxy, etc.

In the present specification, examples of the “aralkyloxy” includebenzyloxy, phenethyloxy, naphthylmethyloxy, fluorenylmethyloxy, etc.;and specifically include C7-C14 aralkyloxy, etc.

In the present specification, the “alkylthio” may be linear or branched.Examples include methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio,hexylthio, etc.; and specifically include C1-C6 alkylthio, C1-C4alkylthio, etc.

In the present specification, examples of the “cycloalkyl-alkylthio”include cyclopropylmethylthio, cyclobutylmethylthio,cyclopentylmethylthio, cyclohexylmethylthio, cycloheptylmethylthio,etc.; and specifically include C3-C7 cycloalkyl-substituted C1-C4alkylthio, etc.

In the present specification, examples of the “monoalkylamino” includemethylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino,isobutylamino, tert-butylamino, n-pentylamino, isopentylamino,hexylamino, etc.; and specifically include amino mono-substituted withlinear or branched C1-C6 alkyl.

In the present specification, examples of the “dialkylamino” includedimethylamino, ethylmethylamino, diethylamino, di(n-propyl)amino,diisopropylamino, di(n-butyl)amino, diisobutylamino,di(tert-butyl)amino, di(n-pentyl)amino, diisopentylamino, dihexylamino,etc.; and specifically include amino di-substituted with linear orbranched C1-C6 alkyl.

In the present specification, examples of the “cycloalkyl-alkylamino”include cyclopropylmethylamino, cyclobutylmethylamino,cyclopentylmethylamino, cyclohexylmethylamino, cycloheptylmethylamino,etc.; and specifically include C3-C7 cycloalkyl-substituted C1-C4alkylamino, etc.

In the present specification, the “acyl” refers to alkylcarbonyl orarylcarbonyl.

In the present specification, examples of the “alkylcarbonyl” includemethylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl,isopentylcarbonyl, hexylcarbonyl, etc.; and specifically include linearor branched (C1-C6 alkyl)carbonyl, etc.

In the present specification, examples of the “arylcarbonyl” includephenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl,biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl,2,3-dihydro-1,4-dioxanaphthalenylcarbonyl, indanylcarbonyl,phenanthrylcarbonyl, etc.; and specifically include (C6-C14aryl)carbonyl, etc.

In the present specification, the “acyloxy” refers to alkylcarbonyloxyor arylcarbonyloxy.

In the present specification, examples of the “alkylcarbonyloxy” includemethylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy,isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy,tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy,hexylcarbonyloxy, etc.; and specifically include linear or branched(C1-C6 alkyl)carbonyloxy, etc.

In the present specification, examples of the “arylcarbonyloxy” includephenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy,anthrylcarbonyloxy, biphenylylcarbonyloxy,tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy,2,3-dihydro-1,4-dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy,phenanthrylcarbonyloxy, etc.; and specifically include (C6-C14aryl)carbonyloxy, etc.

In the present specification, the “alkoxycarbonyl” may be linear orbranched. Examples include methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl,hexyloxycarbonyl, etc.; and specifically include (C1-C6 alkoxy)carbonyl,etc.

In the present specification, examples of the “aralkyloxycarbonyl”include benzyloxycarbonyl, phenethyloxycarbonyl,naphthylmethyloxycarbonyl, fluorenylmethyloxycarbonyl, etc.; andspecifically include (C7-C14 aralkyl)oxycarbonyl, etc.

In the present specification, the “saturated heterocyclic group” refersto a monocyclic or polycyclic saturated heterocyclic group having aheteroatom selected from nitrogen, oxygen, and sulfur. Specific examplesinclude morpholino, 1-pyrrolidinyl, piperidino, piperazinyl,4-methyl-1-piperazinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, thiazolidinyl, oxazolidinyl,7-azabicyclo[2.2.1]hept-2-yl, 2,6-dioxabicyclo[3.2.1]oct-7-yl, etc. Inthe present invention, examples of the saturated heterocyclic groupinclude a “C3-C10 monocyclic or polycyclic saturated heterocyclic groupcontaining 1 to 3 identical or different heteroatoms selected fromnitrogen, oxygen, and sulfur,” a “C3-C6 monocyclic saturatedheterocyclic group containing 1 to 3 identical or different heteroatomsselected from nitrogen, oxygen, and sulfur,” and a “C4-C5 monocyclicsaturated heterocyclic group containing 1 to 3 identical or differentheteroatoms selected from nitrogen and oxygen.”

In the present specification, the “unsaturated heterocyclic group”refers to a monocyclic or polycyclic, completely or partiallyunsaturated heterocyclic group having a heteroatom selected fromnitrogen, oxygen, and sulfur. Specific examples include imidazolyl,thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,isothiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl,pyrazyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl,triazolopyridyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl,benzothienyl, benzofuranyl, purinyl, quinolyl, isoquinolyl,quinazolinyl, quinoxalinyl, methylenedioxyphenyl, ethylenedioxyphenyl,dihydrobenzofuranyl, etc. In the present invention, examples of theunsaturated heterocyclic group include a “C3-C10 monocyclic orpolycyclic unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur,” a“C3-C6 monocyclic unsaturated heterocyclic group containing 1 to 3identical or different heteroatoms selected from nitrogen, oxygen, andsulfur,” a “C4-C5 monocyclic unsaturated heterocyclic group containing 1or 2 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur,” a “C4-C5 monocyclic unsaturated heterocyclic groupcontaining one nitrogen atom, one oxygen atom, or one sulfur atom,” a“C4-C5 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom,” and a “C3-C6 monocyclic unsaturatedheterocyclic group containing 1 to 3 nitrogen atoms.”

In the present specification, the “aromatic hydrocarbon” (aryl) includephenyl, tolyl, xylyl, naphthyl, anthracenyl, phenanthryl, fluorenyl,tetrahydronaphthyl, etc.; and specifically include C6-C14 aromatichydrocarbon, etc.

In the present specification, the “saturated heterocyclic oxy” refers tooxy to which a saturated heterocyclic ring having a heteroatom selectedfrom nitrogen, oxygen, and sulfur is bonded. Specific examples includemorpholinyloxy, 1-pyrrolidinyloxy, piperidinooxy, piperazinyloxy,4-methyl-1-piperazinyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy,tetrahydrothiophenyloxy, thiazolidinyloxy, and oxazolidinyloxy.

The term “Ca-Cb” in the description regarding the substituent in thepresent specification indicates that the substituent has a- to b-numberof carbon atoms. For example, “C1-C6 alkyl” refers to alkyl having 1 to6 carbon atoms, and “C6-C14 aromatic hydrocarbon oxy” refers to oxy towhich C6-C14 aromatic hydrocarbon is bonded. Further, the term “a- tob-membered” indicates that the number of atoms (number of ring members)that constitute the ring is a to b. For example, a “4- to 10-memberedsaturated heterocyclic group” refers to a saturated heterocyclic groupwith a 4- to 10-membered ring.

In Formulas (I) and (I′), A is pyrazolyl substituted with n-number ofR¹. Examples of the pyrazolyl represented by A include pyrazol-1-yl,pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl. Pyrazol-3-yl is preferredin the present invention.

In Formulas (I) and (I′), examples of the “halogen” represented by R¹include those mentioned above, preferably chlorine and bromine, and morepreferably bromine.

In Formulas (I) and (I′), examples of the “C1-C6 alkyl” in the“substituted or unsubstituted C1-C6 alkyl” represented by R¹ includethose mentioned above, and preferably C1-C4 alkyl. Specific examplesinclude methyl, ethyl, n-propyl, isopropyl, etc.; more preferably methyland ethyl; and even more preferably methyl.

Examples of the “substituent” in the “substituted or unsubstituted C1-C6alkyl” represented by R¹ include those mentioned above, and preferablyhalogen and C1-C4 alkoxy. Specific examples include fluorine, methoxy,etc.; more preferably halogen; and even more preferably fluorine.

When the C1-C6 alkyl is substituted, the number of substituents is notparticularly limited, but is preferably 1 to 3. When the substituent ishalogen, the number of substituents is preferably 2 or 3. When thesubstituent is C1-C4 alkoxy, the number of substituents is preferably 1.

The “substituted or unsubstituted C1-C6 alkyl” represented by R¹ ispreferably C1-C6 alkyl that may be substituted with halogen or C1-C4alkoxy. Specific examples include methyl, ethyl, n-propyl, isopropyl,trifluoromethyl, difluoromethyl, methoxymethyl, etc.; more preferablyC1-C6 alkyl that may be substituted with halogen; even more preferablyC1-C4 alkyl that may be substituted with halogen; still more preferablyC1-C4 alkyl that may be substituted with fluorine; further still morepreferably C1-C4 alkyl; and further still more preferably methyl.

In Formulas (I) and (I′), examples of the “C3-C7 cycloalkyl” in the“substituted or unsubstituted C3-C7 cycloalkyl” represented by R¹include those mentioned above; preferably cyclopropyl, cyclobutyl, andcyclopentyl; and more preferably cyclopropyl.

Examples of the “substituent” in the “substituted or unsubstituted C3-C7cycloalkyl” represented by R¹ include those mentioned above.

The “substituted or unsubstituted C3-C7 cycloalkyl” represented by R¹ ispreferably C3-C7 cycloalkyl. Specific examples include cyclopropyl,cyclobutyl, cyclopentyl, etc.; more preferably C3-C5 cycloalkyl; andeven more preferably cyclopropyl.

In Formulas (I) and (I′), examples of the “C6-C14 aromatic hydrocarbon”in the “substituted or unsubstituted C6-C14 aromatic hydrocarbon”represented by R¹ include those mentioned above, and preferably phenyl.

Examples of the “substituent” in the “substituted or unsubstitutedC6-C14 aromatic hydrocarbon” represented by R¹ include those mentionedabove.

The “substituted or unsubstituted C6-C14 aromatic hydrocarbon”represented by R¹ is preferably phenyl.

In Formulas (I) and (I′), the “C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur” in the“substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur”represented by R¹ is preferably a C3-C6 monocyclic unsaturatedheterocyclic group containing one oxygen atom or one sulfur atom; morepreferably a C4-C5 monocyclic unsaturated heterocyclic group containingone oxygen atom or one sulfur atom; even more preferably thienyl andfuranyl; still more preferably the following:

wherein * represents a bonding position (hereinafter the same) andfurther still more preferably the following:

Examples of the “substituent” in the “substituted or unsubstitutedC3-C10 monocyclic or polycyclic saturated or unsaturated heterocyclicgroup containing 1 to 3 identical or different heteroatoms selected fromnitrogen, oxygen, and sulfur” represented by R¹ include those mentionedabove.

The “substituted or unsubstituted C3-C10 monocyclic or polycyclicsaturated or unsaturated heterocyclic group containing 1 to 3 identicalor different heteroatoms selected from nitrogen, oxygen, and sulfur”represented by R¹ is preferably a C3-C6 monocyclic unsaturatedheterocyclic group containing one oxygen atom or one sulfur atom; morepreferably a C4-C5 monocyclic unsaturated heterocyclic group containingone oxygen atom or one sulfur atom; even more preferably thienyl orfuranyl; still more preferably the following:

and further still more preferably the following:

In Formulas (I) and (I′), R¹ is preferably

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur.

R¹ is more preferably

halogen;

cyano;

C1-C6 alkyl that may be substituted with halogen or C1-C4 alkoxy;

C3-C7 cycloalkyl;

phenyl; or

a C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom.

R¹ is even more preferably

halogen;

cyano;

C1-C6 alkyl that may be substituted with halogen;

C3-C7 cycloalkyl;

phenyl; or

a C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom.

R¹ is still more preferably

halogen,

cyano, or

C1-C4 alkyl that may be substituted with halogen.

R¹ is further still more preferably halogen or C1-C4 alkyl.

R¹ is further still more preferably methyl.

In Formulas (I) and (I′), examples of the “C1-C10 alkyl” in the“substituted or unsubstituted C1-C10 alkyl” represented by R² includethose mentioned above; preferably linear C1-C6 alkyl or branched C3-C8alkyl; more preferably linear C1-C4 alkyl or branched C3-C8 alkyl; evenmore preferably linear C1-C4 alkyl or branched C3-C6 alkyl; and stillmore preferably branched C3-C6 alkyl.

The linear C1-C4 alkyl is preferably methyl, ethyl, or n-propyl; andmore preferably methyl.

The branched C3-C8 alkyl is preferably isobutyl, isopropyl, sec-butyl,tert-butyl, tert-pentyl, 1,1,2,2,-tetramethylpropyl,1,1,2,2,-tetramethylethyl, or 1,1-diethylmethyl; and more preferablyisopropyl or tert-butyl.

In Formulas (I) and (I′), examples of the “substituent” in the“substituted or unsubstituted C1-C10 alkyl” represented by R² includethose mentioned above. The substituent is preferably halogen, C3-C7cycloalkyl that may be substituted with C1-C4 alkyl, phenyl, C1-C6alkoxy, or one or more C3-C10 monocyclic or polycyclic unsaturatedheterocyclic groups containing 1 to 3 identical or different heteroatomsselected from nitrogen, oxygen, and sulfur;

more preferably halogen, C3-C7 cycloalkyl that may be substituted withC1-C4 alkyl, phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclicunsaturated heterocyclic groups containing one oxygen atom or one sulfuratom; and

even more preferably fluorine, C3-C7 cycloalkyl that may be substitutedwith C1-C4 alkyl, phenyl, methoxy, or one or more C3-C6 monocyclicunsaturated heterocyclic groups containing one oxygen atom or one sulfuratom.

Specific examples include fluorine, cyclopropyl, cyclopropyl substitutedwith methyl, cyclobutyl, cyclopentyl, phenyl, methoxy, thienyl, etc.;more preferably fluorine, cyclopropyl, cyclobutyl, cyclopentyl, methoxy,and the following:

and even more preferably fluorine and cyclopropyl.

When the C1-C10 alkyl is substituted, the number of substituents is notparticularly limited, but is preferably 1 to 3.

When the C1-C10 alkyl is substituted with “halogen,” the number ofsubstituents is preferably 1 to 3; when the C1-C10 alkyl is substitutedwith “C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,” thenumber of substituents is preferably 1; when the C1-C10 alkyl issubstituted with “phenyl,” the number of substituents is preferably 1;when the C1-C10 alkyl is substituted with “C1-C6 alkoxy,” the number ofsubstituents is preferably 1; and when the C1-C10 alkyl is substitutedwith a “C3-C10 monocyclic or polycyclic unsaturated heterocyclic groupcontaining 1 to 3 identical or different heteroatoms selected fromnitrogen, oxygen, and sulfur,” the number of substituents is preferably1.

The “substituted or unsubstituted C1-C10 alkyl” represented by R² ispreferably C1-C10 alkyl that may be substituted with halogen, C3-C7cycloalkyl that may be substituted with C1-C4 alkyl, phenyl, C1-C6alkoxy, or one or more C3-C10 monocyclic or polycyclic unsaturatedheterocyclic groups containing 1 to 3 identical or different heteroatomsselected from nitrogen, oxygen, and sulfur;

more preferably linear C1-C6 alkyl or branched C3-C8 alkyl that may besubstituted with halogen, C3-C7 cycloalkyl that may be substituted withC1-C4 alkyl, phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclicunsaturated heterocyclic groups containing one oxygen atom or one sulfuratom;even more preferably linear C1-C4 alkyl that is substituted withfluorine or C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl;orbranched C3-C8 alkyl that may be substituted with fluorine, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one oxygen atom or one sulfur atom, phenyl, or C1-C4 alkoxy.

Specific examples include the following:

and the like.

The “substituted or unsubstituted C1-C10 alkyl” represented by R² ismore preferably linear C1-C4 alkyl that is substituted with C3-C7cycloalkyl, or

branched C3-C6 alkyl that may be substituted with halogen, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one sulfur atom, or C1-C4 alkoxy; and

even more preferably linear C1-C4 alkyl that is substituted with C3-C7cycloalkyl, or

branched C3-C6 alkyl that may be substituted with fluorine, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one sulfur atom, or C1-C4 alkoxy.

Specific examples include the following:

and the like.

The “substituted or unsubstituted C1-C10 alkyl” represented by R² ismore preferably branched C3-C6 alkyl that may be substituted withhalogen or C3-C5 cycloalkyl;

even more preferably branched C3-C6 alkyl that may be substituted withfluorine or C3-C5 cycloalkyl; and

still more preferably isopropyl or tert-butyl that may be substitutedwith fluorine or cyclopropyl.

Specific examples include the following:

and the like.

In Formula (I), examples of the “C3-C7 cycloalkyl” in the “substitutedor unsubstituted C3-C7 cycloalkyl” represented by R² include thosementioned above.

Specific examples include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.; preferably C3-C5 cycloalkyl; more preferably C3-C4cycloalkyl; and even more preferably cyclopropyl.

In Formula (I′), examples of the “C3-C4 cycloalkyl” in the “substitutedor unsubstituted C3-C4 cycloalkyl” represented by R² include thosementioned above.

Specific examples include cyclopropyl, cyclobutyl, etc.; and preferablycyclopropyl.

In Formulas (I) and (I′), examples of the “substituent” in the“substituted or unsubstituted C3-C7 cycloalkyl” represented by R²include those mentioned above; and preferably halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, and C3-C5 cycloalkyl.

Specific examples include fluorine, methyl, ethyl, fluoromethyl,difluoromethyl, cyclopropyl, etc.; and more preferably halogen, C1-C4alkyl, and C3-C5 cycloalkyl.

Specific examples include fluorine, methyl, and cyclopropyl; and morepreferably methyl.

When the above C3-C7 cycloalkyl or C3-C4 cycloalkyl is substituted, thenumber of substituents is not particularly limited, but is preferably 1or 2.

When the C3-C7 cycloalkyl is substituted with “halogen,” the number ofsubstituents is preferably 1 or 2.

When the C3-C7 cycloalkyl is substituted with “C1-C4 alkyl,” the numberof substituents is preferably 1 or 2.

When the C3-C7 cycloalkyl is substituted with “halogeno C1-C4 alkyl,”the number of substituents is preferably 1.

When the C3-C7 cycloalkyl is substituted with “C3-C5 cycloalkyl,” thenumber of substituents is preferably 1.

In Formula (I), the “substituted or unsubstituted C3-C7 cycloalkyl”represented by R² is preferably C3-C7 cycloalkyl that may be substitutedwith halogen, C1-C4 alkyl, halogeno C1-C4 alkyl, or C3-C5 cycloalkyl.

Specific examples include the following:

and the like.

The “substituted or unsubstituted C3-C7 cycloalkyl” represented by R² ismore preferably C3-C7 cycloalkyl that may be substituted with halogen,C1-C4 alkyl, or C3-C5 cycloalkyl; and even more preferably C3-C7cycloalkyl that may be substituted with fluorine, C1-C4 alkyl, or C3-C5cycloalkyl.

Specific examples include the following:

and the like.

The “substituted or unsubstituted C3-C7 cycloalkyl” represented by R² ismore preferably C3-C5 cycloalkyl that may be substituted with C1-C4alkyl;

even more preferably C3-C5 cycloalkyl that may be substituted withmethyl;

still more preferably cyclopropyl that may be substituted with methyl;and

further still more preferably the following:

In Formula (I′), the “substituted or unsubstituted C3-C4 cycloalkyl”represented by R² is preferably C3-C4 cycloalkyl that may be substitutedwith halogen, C1-C4 alkyl, halogeno C1-C4 alkyl, or C3-C5 cycloalkyl.

Specific examples include the following:

and the like.

The “substituted or unsubstituted C3-C4 cycloalkyl” represented by R² ismore preferably C3-C4 cycloalkyl that may be substituted with halogen,C1-C4 alkyl, or C3-C5 cycloalkyl; and

even more preferably C3-C4 cycloalkyl that may be substituted withfluorine, C1-C4 alkyl, or C3-C5 cycloalkyl.

Specific examples include the following:

and the like.

The “substituted or unsubstituted C3-C4 cycloalkyl” represented by R² ismore preferably C3-C4 cycloalkyl that may be substituted with C1-C4alkyl,

even more preferably C3-C4 cycloalkyl that may be substituted withmethyl,

still more preferably cyclopropyl that may be substituted with methyl,and

further still more preferably the following:

In Formulas (I) and (I′), examples of the “C2-C6 alkenyl” in the“substituted or unsubstituted C2-C6 alkenyl” represented by R² includethose mentioned above, preferably C2-C4 alkenyl, and more preferablyisopropenyl.

In Formulas (I) and (I′), examples of the “substituent” in the“substituted or unsubstituted C2-C6 alkenyl” represented by R² includethose mentioned above, preferably halogen, and more preferably fluorine.

When the C2-C6 alkenyl is substituted, the number of substituents is notparticularly limited, but is preferably 1 to 3. When the substituent ishalogen, the number of substituents is preferably 1.

In Formulas (I) and (I′), the “substituted or unsubstituted C2-C6alkenyl” represented by R² is preferably C2-C6 alkenyl that may besubstituted with halogen;

more preferably C2-C6 alkenyl that may be substituted with fluorine; and

even more preferably the following:

In Formulas (I) and (I′), examples of the “C3-C7 cycloalkenyl” and“C3-C4 cycloalkenyl” in the “substituted or unsubstituted C3-C7cycloalkenyl” and “substituted or unsubstituted C3-C4 cycloalkenyl”represented by R² include those mentioned above, preferably C3-C4cycloalkenyl, and more preferably cyclobutenyl.

In Formulas (I) and (I′), examples of the “substituent” in the“substituted or unsubstituted C3-C7 cycloalkenyl” and “substituted orunsubstituted C3-C4 cycloalkenyl” represented by R² include thosementioned above, preferably halogen, and more preferably fluorine.

When the C3-C7 cycloalkenyl or C3-C4 cycloalkenyl is substituted, thenumber of substituents is not particularly limited, but is preferably 1to 3. When the substituent is halogen, the number of substituents ispreferably 1.

In Formula (I), the “substituted or unsubstituted C3-C7 cycloalkenyl”represented by R² is preferably C3-C7 cycloalkenyl that may besubstituted with halogen, and

more preferably C3-C4 cycloalkenyl that may be substituted with halogen.

In Formula (I′), the “substituted or unsubstituted C3-C4 cycloalkenyl”represented by R² is preferably C3-C4 cycloalkenyl that may besubstituted with halogen.

In Formulas (I) and (I′), examples of the “C4-C12 bridged cycloalkyl” inthe “substituted or unsubstituted C4-C12 bridged cycloalkyl” representedby R² include those mentioned above;

preferably bicyclo[1.1.1]pentan-1-yl, bicyclo[2.2.1]heptan-2-yl,adamantan-2-yl, and bicyclo[3.1.1]heptan-3-yl;

more preferably bicyclo[1.1.1]pentan-1-yl, bicyclo[2.2.1]heptan-2-yl,and adamantan-2-yl;

even more preferably bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl; and

still more preferably bicyclo[2.2.1]heptan-2-yl.

In Formulas (I) and (I′), examples of the “substituent” in the“substituted or unsubstituted C4-C12 bridged cycloalkyl” represented byR² include those mentioned above, preferably C1-C4 alkyl, and morepreferably methyl.

When the C4-C12 bridged cycloalkyl is substituted, the number ofsubstituents is not particularly limited, but is preferably 1 to 3. Whenthe substituent is C1-C4 alkyl, the number of substituents is preferably1 to 3, and more preferably 3.

In Formulas (I) and (I′), the “substituted or unsubstituted C4-C12bridged cycloalkyl” represented by R² is preferably C4-C12 bridgedcycloalkyl that may be substituted with C1-C4 alkyl; and

more preferably C4-C12 bridged cycloalkyl that may be substituted withmethyl and is selected from bicyclo[1.1.1]pentan-1-yl,bicyclo[2.2.1]heptan-2-yl, adamantan-2-yl, andbicyclo[3.1.1]heptan-3-yl.

Specific examples include bicyclo[1.1.1]pentan-1-yl,bicyclo[2.2.1]heptan-2-yl, adamantan-2-yl,2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl, etc.

The “substituted or unsubstituted C4-C12 bridged cycloalkyl” representedby R² is more preferably C4-C12 bridged cycloalkyl;

even more preferably bicyclo[1.1.1]pentan-1-yl orbicyclo[2.2.1]heptan-2-yl; and

still more preferably bicyclo[2.2.1]heptan-2-yl.

In Formulas (I) and (I′), examples of the “C6-C14 aromatic hydrocarbon”in the “substituted or unsubstituted C6-C14 aromatic hydrocarbon”represented by R² include those mentioned above, and preferably phenyl.

Examples of the “substituent” in the “substituted or unsubstitutedC6-C14 aromatic hydrocarbon” represented by R² include those mentionedabove.

The “substituted or unsubstituted C6-C14 aromatic hydrocarbon”represented by R² is preferably phenyl.

In Formulas (I) and (I′), the “C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur” in the“substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur”represented by R² is preferably a C3-C6 monocyclic unsaturatedheterocyclic group containing one nitrogen atom, one oxygen atom, or onesulfur atom;

more preferably a C4-C5 monocyclic unsaturated heterocyclic groupcontaining one nitrogen atom, one oxygen atom, or one sulfur atom; and

even more preferably thienyl or furanyl.

Examples of the “substituent” in the “substituted or unsubstitutedC3-C10 monocyclic or polycyclic saturated or unsaturated heterocyclicgroup containing 1 to 3 identical or different heteroatoms selected fromnitrogen, oxygen, and sulfur” represented by R² include those mentionedabove.

The “substituted or unsubstituted C3-C10 monocyclic or polycyclicsaturated or unsaturated heterocyclic group containing 1 to 3 identicalor different heteroatoms selected from nitrogen, oxygen, and sulfur”represented by R² is preferably a C3-C6 monocyclic unsaturatedheterocyclic group containing one nitrogen atom, one oxygen atom, or onesulfur atom;

more preferably a C4-C5 monocyclic unsaturated heterocyclic groupcontaining one nitrogen atom, one oxygen atom, or one sulfur atom; and

even more preferably thienyl or furanyl.

R² in Formula (I) is preferably,

substituted or unsubstituted C1-C10 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C4-C12 bridged cycloalkyl.

R² is more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl that may be substituted with C1-C4 alkyl.

R² is even more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; or C4-C12 bridgedcycloalkyl.

R² is still more preferably

linear C1-C4 alkyl that is substituted with C3-C7 cycloalkyl;

branched C3-C6 alkyl that may be substituted with halogen, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one sulfur atom, or C1-C4 alkoxy;

C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl, orC3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with halogen; or

C4-C12 bridged cycloalkyl selected from bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl.

R² is further still more preferably

branched C3-C6 alkyl that may be substituted with halogen or C3-C5cycloalkyl;

C3-C5 cycloalkyl that may be substituted with C1-C4 alkyl, orbicyclo[2.2.1]heptan-2-yl.

R² is further still more preferably

isopropyl or tert-butyl that may be substituted with fluorine orcyclopropyl, or

cyclopropyl that may be substituted with methyl.

Moreover, R² in Formula (I′) is preferably

substituted or unsubstituted C1-C10 alkyl,

substituted or unsubstituted C3-C4 cycloalkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C4-C12 bridged cycloalkyl.

R² is more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl that may be substituted with C1-C4 alkyl.

R² is even more preferably linear C1-C6 alkyl or branched C3-C8 alkylthat may be substituted with halogen, C3-C7 cycloalkyl that may besubstituted with C1-C4 alkyl, phenyl, C1-C4 alkoxy, or one or more C3-C6monocyclic unsaturated heterocyclic groups containing one oxygen atom orone sulfur atom;

C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with halogen; or

C4-C12 bridged cycloalkyl.

R² is still more preferably

linear C1-C4 alkyl that is substituted with C3-C7 cycloalkyl;

branched C3-C6 alkyl that may be substituted with halogen, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one sulfur atom, or C1-C4 alkoxy;

C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl, orC3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with halogen; or

C4-C12 bridged cycloalkyl selected from bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl.

R² is further still more preferably

branched C3-C6 alkyl that may be substituted with halogen or C3-C5cycloalkyl;

C3-C4 cycloalkyl that may be substituted with C1-C4 alkyl; orbicyclo[2.2.1]heptan-2-yl.

R² is further still more preferably

isopropyl or tert-butyl that may be substituted with fluorine orcyclopropyl, or

cyclopropyl that may be substituted with methyl.

In Formulas (I) and (I′), X is N or CR³, and preferably CR³.

In Formulas (I) and (I′), examples of the “halogen” represented by R³include those mentioned above, and preferably bromine and chlorine.

In Formulas (I) and (I′), examples of the “C1-C6 alkyl” in the“substituted or unsubstituted C1-C6 alkyl” represented by R³ includethose mentioned above, preferably C1-C4 alkyl, and more preferablymethyl.

Examples of the “substituent” in the “substituted or unsubstituted C1-C6alkyl” represented by R³ include those mentioned above.

The “substituted or unsubstituted C1-C6 alkyl” represented by R³ ispreferably C1-C6 alkyl, more preferably C1-C4 alkyl, and even morepreferably methyl.

In Formulas (I) and (I′), examples of the “C2-C6 alkenyl” in the“substituted or unsubstituted C2-C6 alkenyl” represented by R³ includethose mentioned above, and preferably vinyl and isopropenyl.

Examples of the “substituent” in the “substituted or unsubstituted C2-C6alkenyl” represented by R³ include those mentioned above.

In Formulas (I) and (I′), the “substituted or unsubstituted C2-C6alkenyl” represented by R³ is preferably vinyl or isopropenyl.

Examples of the “C2-C6 alkynyl” in the “substituted or unsubstitutedC2-C6 alkynyl” represented by R³ include those mentioned above,preferably C2-C4 alkynyl, and more preferably ethynyl or propynyl.

The number of triple bonds in the “C2-C6 alkynyl” is preferably 1, andthe triple bond is preferably positioned between a carbon atom bonded toa 7H-pyrrolo[2,3-d]pyrimidine skeleton and a carbon atom adjacent to thecarbon atom.

Examples of the “substituent” in the “substituted or unsubstituted C2-C6alkynyl” represented by R³ include those mentioned above; and preferably

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C10 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C10 monocyclic or polycyclic unsaturated heterocyclicgroups that may be substituted with C1-C6 alkyl and contains 1 to 3identical or different heteroatoms selected from nitrogen, oxygen, andsulfur.

Specific examples include

hydroxyisopropyl,

hydroxycyclopentyl,

hydroxycyclobutyl,

morpholino,

tetrahydropyranyl,

pyrazolyl that may be substituted with methyl,imidazo[1,2-b]pyridazinyl,

imidazolyl that may be substituted with methyl, and pyridinyl.

The “substituent” is more preferably

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C10 monocyclic or polycyclic unsaturated heterocyclicgroups that may be substituted with C1-C6 alkyl and contains 1 to 3identical or different heteroatoms selected from nitrogen, oxygen, andsulfur.

The “substituent” is even more preferably

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C6 monocyclic unsaturated heterocyclic groups that may besubstituted with C1-C4 alkyl and contains 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur.

The “substituent” is still more preferably

C1-C4 alkyl that may be substituted with hydroxy,

C3-C5 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen andoxygen, or

one or more C3-C6 monocyclic unsaturated heterocyclic groups that may besubstituted with methyl and contains 1 to 3 nitrogen atoms.

The “substituent” is further still more preferably

isopropyl that may be substituted with hydroxy,

C3-C5 cycloalkyl that may be substituted with hydroxy,

one or more C4-C5 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen andoxygen, or

one or more C3-C6 monocyclic unsaturated heterocyclic groups that may besubstituted with methyl and contains 1 to 3 nitrogen atoms.

The “substituted or unsubstituted C2-C6 alkynyl” represented by R³ ispreferably C2-C4 alkynyl that may be substituted with

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C10 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C10 monocyclic or polycyclic unsaturated heterocyclicgroups that may be substituted with C1-C6 alkyl and contains 1 to 3identical or different heteroatoms selected from nitrogen, oxygen, andsulfur.

Specific examples include the following:

The “substituted or unsubstituted C2-C6 alkynyl” represented by R³ ismore preferably C2-C4 alkynyl that may be substituted with

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C10 monocyclic or polycyclic unsaturated heterocyclicgroups that may be substituted with C1-C6 alkyl and contains 1 to 3identical or different heteroatoms selected from nitrogen, oxygen, andsulfur.

The “substituted or unsubstituted C2-C6 alkynyl” represented by R³ iseven more preferably C2-C4 alkynyl that is substituted with

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C6 monocyclic unsaturated heterocyclic groups that may besubstituted with C1-C4 alkyl and contains 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur.

The “substituted or unsubstituted C2-C6 alkynyl” represented by R³ isstill more preferably ethynyl or propynyl that is substituted with

C1-C4 alkyl that may be substituted with hydroxy,

C3-C5 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen andoxygen, or

one or more C3-C6 monocyclic unsaturated heterocyclic groups that may besubstituted with methyl and contains 1 to 3 nitrogen atoms.

The “substituted or unsubstituted C2-C6 alkynyl” represented by R³ isfurther still more preferably ethynyl or propynyl that is substitutedwith

isopropyl that may be substituted with hydroxy,

C3-C5 cycloalkyl that may be substituted with hydroxy,

one or more C4-C5 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen andoxygen, or

one or more C3-C6 monocyclic unsaturated heterocyclic groups that may besubstituted with methyl and contains 1 to 3 nitrogen atoms.

Examples of the “C1-C6 alkoxy” in the “substituted or unsubstitutedC1-C6 alkoxy” represented by R³ include those mentioned above,preferably C1-C4 alkoxy, and more preferably methoxy.

Examples of the “substituent” in the “substituted or unsubstituted C1-C6alkoxy” represented by R³ include those mentioned above;

preferably one or more C3-C10 monocyclic saturated heterocyclic groupscontaining 1 to 3 identical or different heteroatoms selected fromnitrogen, oxygen, and sulfur; and

more preferably one or more C3-C6 monocyclic saturated heterocyclicgroups containing one oxygen atom.

The “substituted or unsubstituted C1-C6 alkoxy” represented by R³ isC1-C4 alkoxy that may be substituted with one or more C3-C10 monocyclicsaturated heterocyclic groups containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur, or

C1-C4 alkoxy that may be substituted with one or more C3-C6 monocyclicsaturated heterocyclic groups containing one oxygen atom;

more preferably C1-C4 alkoxy; and

even more preferably methoxy.

In Formulas (I) and (I′), examples of the “substituent” in the“substituted or unsubstituted amino” represented by R³ include thosementioned above.

In Formulas (I) and (I′), the “C6-C14 aromatic hydrocarbon” in the“substituted or unsubstituted C6-C14 aromatic hydrocarbon” representedby R³ include those mentioned above, and preferably phenyl.

Examples of the “substituent” in the “substituted or unsubstitutedC6-C14 aromatic hydrocarbon” represented by R³ include those mentionedabove.

In Formulas (I) and (I′), the “substituted or unsubstituted C6-C14aromatic hydrocarbon” represented by R³ is preferably phenyl.

In Formulas (I) and (I′), the “C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur” in the“substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur”represented by R³ is preferably a C3-C6 monocyclic unsaturatedheterocyclic group containing one oxygen atom or one sulfur atom, andmore preferably thienyl or furanyl.

Examples of the “substituent” in the “substituted or unsubstitutedC3-C10 monocyclic or polycyclic saturated or unsaturated heterocyclicgroup containing 1 to 3 identical or different heteroatoms selected fromnitrogen, oxygen, and sulfur” represented by R³ include those mentionedabove.

The “substituted or unsubstituted C3-C10 monocyclic or polycyclicsaturated or unsaturated heterocyclic group containing 1 to 3 identicalor different heteroatoms selected from nitrogen, oxygen, and sulfur”represented by R³ is preferably a C3-C6 monocyclic unsaturatedheterocyclic group containing one oxygen atom or one sulfur atom, andmore preferably thienyl or furanyl.

R³ is preferably

hydrogen,

halogen,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C1-C6 alkoxy.

R³ is more preferably

hydrogen;

halogen;

C1-C6 alkyl;

C2-C4 alkynyl that may be substituted with

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C10 monocyclic or polycyclic unsaturated heterocyclicgroups that may be substituted with C1-C6 alkyl and contains 1 to 3identical or different heteroatoms selected from nitrogen, oxygen, andsulfur; or

C1-C4 alkoxy that may be substituted with one or more C3-C6 monocyclicsaturated heterocyclic groups containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur.

R³ is even more preferably

hydrogen;

halogen;

C1-C4 alkyl;

C2-C4 alkynyl that may be substituted with

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C10 monocyclic or polycyclic unsaturated heterocyclicgroups that may be substituted with C1-C6 alkyl and contains 1 to 3identical or different heteroatoms selected from nitrogen, oxygen, andsulfur; or

C1-C4 alkoxy.

R³ is still more preferably

hydrogen; or

C2-C4 alkynyl that is substituted with

C1-C6 alkyl that may be substituted with hydroxy,

C3-C7 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen, oxygen,and sulfur, or

one or more C3-C6 monocyclic unsaturated heterocyclic groups that may besubstituted with C1-C4 alkyl and contains 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur.

R³ is further still more preferably

hydrogen; or

ethynyl or propynyl that is substituted with

C1-C4 alkyl that may be substituted with hydroxy,

C3-C5 cycloalkyl that may be substituted with hydroxy,

one or more C3-C6 monocyclic saturated heterocyclic groups containing 1to 3 identical or different heteroatoms selected from nitrogen andoxygen, or

one or more C3-C6 monocyclic unsaturated heterocyclic groups that may besubstituted with methyl and contains 1 to 3 nitrogen atoms.

R³ is further still more preferably hydrogen.

In Formulas (I) and (I′), n is an integer of 0 to 3, preferably 0 to 2,more preferably 1 or 2, and even more preferably 1.

When n is 2 or 3, R¹ may be identical or different from each other, andis preferably identical.

In Formulas (I) and (I′), the bonding position between the amidestructure and the pyrazolyl group is preferably as shown in Formulas(II) and (II′) below.

Moreover, when n is 1, the bonding position between the substituent R¹and the pyrazolyl group is preferably as shown in Formulas (VIII) and(VIII′) below.

When n is 1, the bonding position between the substituent R¹ and thepyrazolyl group is more preferably as shown in Formulas (IX) and (IX′)below:

[1] The present invention provides a compound represented by Formula (I)below or a salt thereof:

wherein A is pyrazolyl substituted with n-number of R¹;R¹ ishalogen,cyano,substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;R² issubstituted or unsubstituted C1-C10 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C2-C6 alkenyl,substituted or unsubstituted C3-C7 cycloalkenyl,substituted or unsubstituted C4-C12 bridged cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;X isN orCR³, wherein R³ is

hydrogen,

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkenyl,

substituted or unsubstituted C2-C6 alkynyl,

substituted or unsubstituted C1-C6 alkoxy,

substituted or unsubstituted amino,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclicunsaturated heterocyclic group containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and

n is an integer of 0 to 3,

wherein when n is 2 or 3, R¹ may be identical or different from eachother.

[2] In Formula (I),

A is preferably pyrazolyl substituted with n-number of R¹;

R¹ is preferably

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;

R² is preferably

substituted or unsubstituted C1-C10 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C4-C12 bridged cycloalkyl;

X is preferably

N or

CR³, wherein R³ is

hydrogen,

halogen,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkynyl, or

substituted or unsubstituted C1-C6 alkoxy; and

n is preferably an integer of 1 to 3,

wherein when n is 2 or 3, R¹ may be identical or different from eachother.

[3] In Formula (I),

A is more preferably pyrazolyl substituted with n-number of R¹;

R¹ is more preferably

halogen;

cyano;

C1-C6 alkyl that may be substituted with halogen or C1-C4 alkoxy;

C3-C7 cycloalkyl;

phenyl; or

a C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom;

R² is more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl that may be substituted with C1-C4 alkyl;X is more preferablyN orCR³, wherein R³ is

hydrogen;

halogen;

C1-C6 alkyl;

-   -   C2-C4 alkynyl that may be substituted with    -   C1-C6 alkyl that may be substituted with hydroxy, C3-C7        cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C10 monocyclic or polycyclic unsaturated        heterocyclic groups that may be substituted with C1-C6 alkyl and        contains 1 to 3 identical or different heteroatoms selected from        nitrogen, oxygen, and sulfur; or

C1-C4 alkoxy that may be substituted with one or more C3-C6 monocyclicsaturated heterocyclic groups containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and

n is more preferably 1 or 2,

wherein when n is 2, R¹ may be identical or different from each other.

In another embodiment of the present invention, a compound of Formula(I) wherein pyrazolyl is bonded to an amide structure at 3-position ispreferable. Moreover, a preferred embodiment of the compound of Formula(I) wherein pyrazolyl is bonded to an amide structure at 3-position inthe present invention is

[4] a compound represented by Formula (II) below or a salt thereof:

wherein R¹ ishalogen,cyano,substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;R² issubstituted or unsubstituted C1-C10 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C2-C6 alkenyl, orsubstituted or unsubstituted C4-C12 bridged cycloalkyl;X isN orCR³, wherein R³ is

hydrogen,

halogen,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C1-C6 alkoxy; and

n is an integer of 1 to 3,

wherein when n is 2 or 3, R¹ may be identical or different from eachother.

In the present invention, the compound represented by Formula (II) aboveis also referred to simply as Compound (II).

[5] In Formula (II),

R¹ is more preferably

halogen;

cyano;

C1-C6 alkyl that may be substituted with halogen or C1-C4 alkoxy;

C3-C7 cycloalkyl;

phenyl; or

a C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom;

R² is more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl that may be substituted with C1-C4 alkyl;X is more preferablyN orCR³, wherein R³ is

hydrogen;

halogen;

C1-C6 alkyl;

C2-C4 alkynyl that may be substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C10 monocyclic or polycyclic unsaturated        heterocyclic groups that may be substituted with C1-C6 alkyl and        contains 1 to 3 identical or different heteroatoms selected from        nitrogen, oxygen, and sulfur; or

C1-C4 alkoxy that may be substituted with one or more C3-C6 monocyclicsaturated heterocyclic groups containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and

n is more preferably 1 or 2,

wherein when n is 2, R¹ may be identical or different from each other.

[6] In Formula (II),

R¹ is more preferably

halogen;

cyano;

C1-C6 alkyl that may be substituted with halogen;

C3-C7 cycloalkyl;

phenyl; or

a C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom;

R² is more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl;X is more preferablyN orCR³, wherein R³ is

hydrogen;

halogen;

C1-C4 alkyl;

C2-C4 alkynyl that may be substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C10 monocyclic or polycyclic unsaturated        heterocyclic groups that may be substituted with C1-C6 alkyl and        contains 1 to 3 identical or different heteroatoms selected from        nitrogen, oxygen, and sulfur; or

C1-C4 alkoxy; and

n is more preferably 1 or 2,

wherein when n is 2, R¹ may be identical or different from each other.

[7] In Formula (II),

R¹ is more preferably

halogen,

cyano, or

C1-C4 alkyl that may be substituted with halogen;

R² is more preferably

linear C1-C4 alkyl that is substituted with C3-C7 cycloalkyl;

branched C3-C6 alkyl that may be substituted with halogen, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one sulfur atom, or C1-C4 alkoxy;

C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl, orC3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with halogen; or

C4-C12 bridged cycloalkyl selected from bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl;

X is more preferably

N or

CR³, wherein R³ is

hydrogen; or

C2-C4 alkynyl that is substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C6 monocyclic unsaturated heterocyclic groups        that may be substituted with C1-C4 alkyl and contains 1 to 3        identical or different heteroatoms selected from nitrogen,        oxygen, and sulfur; and        n is more preferably an integer of 1.

Preferred in another embodiment of the present invention is

[8] a compound represented by Formula (IX) below or a salt thereof:

wherein R¹ ishalogen;cyano;C1-C6 alkyl that may be substituted with halogen;C3-C7 cycloalkyl;phenyl; ora C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom;R² islinear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl;X isN orCR³, wherein R³ is

hydrogen;

halogen;

C1-C4 alkyl;

C2-C4 alkynyl that may be substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C10 monocyclic or polycyclic unsaturated        heterocyclic groups that may be substituted with C1-C6 alkyl and        contains 1 to 3 identical or different heteroatoms selected from        nitrogen, oxygen, and sulfur; or

C1-C4 alkoxy.

In the present invention, the compound represented by Formula (IX) aboveis also referred to simply as Compound (IX).

[9] In Formula (IX),

R¹ is more preferably

halogen,

cyano, or

C1-C4 alkyl that may be substituted with halogen;

R² is more preferably

linear C1-C4 alkyl that is substituted with C3-C7 cycloalkyl;

branched C3-C6 alkyl that may be substituted with halogen, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one sulfur atom, or C1-C4 alkoxy;

C3-C7 cycloalkyl that may be substituted with halogen, C1-C4 alkyl, orC3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with halogen; or

C4-C12 bridged cycloalkyl selected from bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl; and

X is more preferably

N or

CR³, wherein R³ is

hydrogen; or

C2-C4 alkynyl that may be substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C6 monocyclic unsaturated heterocyclic groups        that may be substituted with C1-C4 alkyl and contains 1 to 3        identical or different heteroatoms selected from nitrogen,        oxygen, and sulfur.

[10] In Formula (IX),

R¹ is more preferably

bromine,

cyano, or

C1-C4 alkyl that may be substituted with fluorine;

R² is more preferably

linear C1-C4 alkyl that is substituted with C3-C7 cycloalkyl;

branched C3-C6 alkyl that may be substituted with fluorine, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one sulfur atom, or C1-C4 alkoxy;

C3-C7 cycloalkyl that may be substituted with fluorine, C1-C4 alkyl, orC3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with fluorine; or

C4-C12 bridged cycloalkyl selected from bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl; and

X is more preferably

N or

CR³, wherein R³ is

hydrogen; or

C2-C4 alkynyl that is substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C6 monocyclic unsaturated heterocyclic groups        that may be substituted with C1-C4 alkyl and contains 1 to 3        identical or different heteroatoms selected from nitrogen,        oxygen, and sulfur.

Moreover, in another embodiment of the present invention,

[11] in Formula (IX),

R¹ is more preferably halogen or C1-C4 alkyl;

R² is more preferably

branched C3-C6 alkyl that may be substituted with halogen or C3-C5cycloalkyl,

C3-C5 cycloalkyl that may be substituted with C1-C4 alkyl, orbicyclo[2.2.1]heptan-2-yl; and

X is more preferably

N or

CR³, wherein R³ is

hydrogen; or

ethynyl or propynyl that is substituted with

-   -   C1-C4 alkyl that may be substituted with hydroxy,    -   C3-C5 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen and oxygen, or    -   one or more C3-C6 monocyclic unsaturated heterocyclic groups        that may be substituted with methyl and contains 1 to 3 nitrogen        atoms.

[12] In Formula (IX),

R¹ is more preferably bromine or methyl;

R² is more preferably

branched C3-C6 alkyl that may be substituted with fluorine or C3-C5cycloalkyl, or

C3-C5 cycloalkyl that may be substituted with methyl; and

X is more preferably

N or

CR³, wherein R³ is hydrogen.

[13] In Formula (IX),

R¹ is more preferably methyl;

R² is more preferably

isopropyl or tert-butyl that may be substituted with fluorine orcyclopropyl, or

cyclopropyl that may be substituted with methyl; and

X is more preferably

N or

CR³, wherein R³ is hydrogen.

Moreover,

[14] in Formulas (I), (II), and (IX) of the present invention, when X isN,

R¹ is preferably

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur; and

R² is preferably

substituted or unsubstituted C1-C10 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C4-C12 bridged cycloalkyl.

Moreover,

[15] in Formulas (I), (II), and (IX) of the present invention, when X isCR³ (R³ is as defined above),

R¹ is preferably

halogen,

substituted or unsubstituted C1-C6 alkyl, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur; and

R² is preferably

substituted or unsubstituted C1-C10 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl, or

substituted or unsubstituted C4-C12 bridged cycloalkyl.

Specific examples of the compound of the present invention include, butare not limited to, compounds produced in the Examples described later.

Specific preferred examples of Compound (I) are as follows:

[16]

-   (1)    4-amino-1-cyclopentyl-N-(5-ethyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 1);-   (2)    4-amino-1-cyclopentyl-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 2);-   (3)    4-amino-1-cyclopentyl-N-(5-(furan-3-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 3);-   (4)    4-amino-1-cyclopentyl-N-(5-(thiophen-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 4);-   (5)    4-amino-1-cyclopentyl-N-(5-phenyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 5);-   (6)    4-amino-1-cyclopentyl-N-(5-cyclopentyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 6);-   (7)    4-amino-1-cyclopentyl-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 7);-   (8)    4-amino-1-cyclopentyl-N-(3-propyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 8);-   (9)    4-amino-1-cyclopentyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 9);-   (10)    4-amino-1-cyclopentyl-N-(5-isopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 10);-   (11)    4-amino-1-cyclobutyl-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 11);-   (12)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-((1-methylcyclopropyl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 12);-   (13)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 13);-   (14)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 14);-   (15)    4-amino-1-(sec-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 15);-   (16)    4-amino-1-(cyclobutylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 16);-   (17)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 17);-   (18)    4-amino-1-(cyclopropylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 18);-   (19)    4-amino-1-(cyclopentylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 19);-   (20)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 20);-   (21)    4-amino-1-isopropyl-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 21);-   (22)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 22);-   (23)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 23);-   (24)    4-amino-1-(4,4-dimethylcyclohexyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 24);-   (25)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 25);-   (26)    4-amino-1-(3,3-dimethylcyclobutyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 26);-   (27)    4-amino-1-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 27);-   (28)    4-amino-1-(bicyclo[2.2.1]heptan-2-yl)-N-(5-bromo-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 28);-   (29)    1-(adamantan-2-yl)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 29);-   (30)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-((2S,3R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 30);-   (31)    4-amino-1-(3-fluoroprop-1-en-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 31);-   (32)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 32);-   (33)    4-amino-1-cyclohexyl-N-(5-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 33);-   (34)    4-amino-1-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 34);-   (35)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 35);-   (36)    4-amino-1-(tert-butyl)-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 36);-   (37)    4-amino-1-(tert-butyl)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 37);-   (38)    4-amino-1-(tert-butyl)-N-(5-cyano-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 38);-   (39)    4-amino-1-(tert-butyl)-N-(5-ethyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 39);-   (40)    4-amino-1-(tert-butyl)-N-(5-isopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 40);-   (41)    4-amino-1-(tert-butyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 41);-   (42)    4-amino-1-(tert-butyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 42);-   (43)    4-amino-1-(4,4-difluorocyclohexyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 43);-   (44)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 44);-   (45)    4-amino-7-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 45);-   (46)    4-amino-7-(1-fluoropropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 46);-   (47)    4-amino-7-(4,4-dimethylcyclohexyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 47);-   (48)    4-amino-7-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 48);-   (49)    4-amino-7-(tert-butyl)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 49);-   (50)    4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 50);-   (51)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 51);-   (52)    4-amino-7-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 52);-   (53)    4-amino-7-(1-methoxy-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 53);-   (54)    4-amino-7-(1-(fluoromethyl)cyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 54);-   (55)    4-amino-7-(1-(difluoromethyl)cyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 55);-   (56)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2-(thiophen-2-yl)propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 56);-   (57)    4-amino-7-(3,3-difluorocyclopentyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 57);-   (58)    4-amino-7-(bicyclo[1.1.1]pentan-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 58);-   (59)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 59);-   (60)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2-phenylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 60);-   (61)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2,3,3-trimethylbutan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 61);-   (62)    4-amino-7-(2,3-dimethylbutan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 62);-   (63)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 63);-   (64)    4-amino-7-(tert-butyl)-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 64);-   (65)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 65);-   (66)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 66);-   (67)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 67);-   (68)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 68);-   (69)    4-amino-7-cyclobutyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 69);-   (70)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(tert-pentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 70);-   (71)    4-amino-7-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 71);-   (72)    4-amino-7-cyclopentyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 72);-   (73)    4-amino-7-(tert-butyl)-6-methyl-N-(3-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 73);-   (74)    7-([1,1′-bi(cyclopropan)]-1-yl)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 74);-   (75)    4-amino-6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 75);-   (76)    4-amino-6-bromo-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 76);-   (77)    4-amino-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 77);-   (78)    4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 78);-   (79)    4-amino-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 79);-   (80)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 80);-   (81)    4-amino-6-((1-hydroxycyclopentyl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 81);-   (82)    4-amino-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 82);-   (83)    4-amino-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 83);-   (84)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(3-morpholino-1-propyn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 84);-   (85)    4-amino-6-(3-(1-hydroxycyclobutyl)-1-propyne)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 85);-   (86)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 86);-   (87)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-6-((1-methyl-1H-pyrazol-3-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 87);-   (88)    4-amino-6-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 88);-   (89)    4-amino-6-ethoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 89); and-   (90)    (R)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 90).

More preferred examples of Compound (I) are as follows:

[17]

-   (27)    4-amino-1-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 27);-   (34)    4-amino-1-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 34);-   (45)    4-amino-7-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 45);-   (48)    4-amino-7-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 48);-   (50)    4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 50);-   (51)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 51);-   (52)    4-amino-7-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 52);-   (65)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 65);-   (68)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 68);-   (71)    4-amino-7-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 71);-   (72)    4-amino-7-cyclopentyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 72);-   (79)    4-amino-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 79);-   (80)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 80);-   (81)    4-amino-6-((1-hydroxycyclopentyl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 81);-   (82)    4-amino-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 82);-   (83)    4-amino-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 83);-   (84)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(3-morpholino-1-propyn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 84); and-   (85)    4-amino-6-(3-(1-hydroxycyclobutyl)-1-propyne)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 85).

Even more preferred examples of Compound (I) are as follows:

[18]

-   (34)    4-amino-1-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 34);-   (48)    4-amino-7-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 48);-   (50)    4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 50);-   (51)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 51); and-   (52)    4-amino-7-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 52).

Moreover, the present invention provides a RET inhibitor comprising thecompound or a salt thereof according to any one of [1] to [18] as anactive ingredient.

Moreover, the present invention provides a pharmaceutical compositioncomprising the compound or a salt thereof according to any one of [1] to[18].

Moreover, the present invention provides a pharmaceutical compositioncomprising the compound or a salt thereof according to any one of [1] to[18], wherein the pharmaceutical composition prevents or treats adisease that can be treated by RET inhibition.

Moreover, the present invention provides an antitumor agent comprisingthe compound or a salt thereof according to any one of [1] to [18].

Moreover, the present invention provides an antitumor agent comprisingthe compound or a salt thereof according to any one of [1] to [18],wherein the antitumor agent treats a malignant tumor with enhancedactivation of RET.

Moreover, the present invention provides the compound or a salt thereofaccording to any one of [1] to [18] for use in prevention or treatmentof a malignant tumor.

Moreover, the present invention provides the compound or a salt thereofaccording to any one of [1] to [18] for use in prevention or treatmentof a malignant tumor, wherein the malignant tumor is a malignant tumorwith enhanced activation of RET.

Moreover, the present invention provides use of the compound or a saltthereof according to any one of [1] to [18] for producing an antitumoragent.

Moreover, the present invention provides use of the compound or a saltthereof according to any one of [1] to [18] for producing an antitumoragent, wherein the antitumor agent is an antitumor agent for treating amalignant tumor with enhanced activation of RET.

Moreover, the present invention provides use of the compound or a saltthereof according to any one of [1] to [18] for producing a RETinhibitor.

Moreover, the present invention provides a method for preventing ortreating a malignant tumor, the method comprising administering thecompound or a salt thereof according to any one of [1] to [18] to amammal.

Moreover, the present invention provides a method for preventing ortreating a malignant tumor, the method comprising administering thecompound or a salt thereof according to any one of [1] to [18] to amammal, wherein the malignant tumor is a malignant tumor with enhancedactivation of RET.

Moreover, the present invention provides a method of inhibiting RETcomprising administering the compound or a salt thereof according to anyone of [1] to [18] to a mammal.

Moreover, the present invention provides

[19] a compound represented by Formula (I′) below or a salt thereof:

wherein A is pyrazolyl substituted with n-number of R¹;R¹ ishalogen,cyano,substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;R² issubstituted or unsubstituted C1-C10 alkyl,substituted or unsubstituted C3-C4 cycloalkyl,substituted or unsubstituted C2-C6 alkenyl,substituted or unsubstituted C3-C4 cycloalkenyl,substituted or unsubstituted C4-C12 bridged cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;X isN orCR³, wherein R³ is

hydrogen,

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkenyl,

substituted or unsubstituted C2-C6 alkynyl,

substituted or unsubstituted C1-C6 alkoxy,

substituted or unsubstituted amino,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclicunsaturated heterocyclic group containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and

n is an integer of 0 to 3,

wherein when n is 2 or 3, R¹ may be identical or different from eachother.

[20] In Formula (I′),

A is preferably pyrazolyl substituted with n-number of R¹;

R¹ is preferably

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;

R² is preferably

substituted or unsubstituted C1-C10 alkyl,

substituted or unsubstituted C3-C4 cycloalkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C4-C12 bridged cycloalkyl,

X is preferably

N or

CR³, wherein R³ is

hydrogen,

halogen,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C1-C6 alkoxy; and

n is preferably an integer of 1 to 3,

wherein when n is 2 or 3, R¹ may be identical or different from eachother.

[21] In Formula (I′),

A is pyrazolyl substituted with n-number of R¹;

R¹ is more preferably

halogen;

cyano;

C1-C6 alkyl that may be substituted with halogen or C1-C4 alkoxy;

C3-C7 cycloalkyl;

phenyl; or

a C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom;

R² is more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl that may be substituted with C1-C4 alkyl;X is more preferablyN orCR³, wherein R³ is

hydrogen;

halogen;

C1-C6 alkyl;

C2-C4 alkynyl that may be substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C10 monocyclic or polycyclic unsaturated        heterocyclic groups that may be substituted with C1-C6 alkyl and        contains 1 to 3 identical or different heteroatoms selected from        nitrogen, oxygen, and sulfur; or

C1-C4 alkoxy that may be substituted with one or more C3-C6 monocyclicsaturated heterocyclic groups containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and

n is more preferably 1 or 2,

wherein when n is 2, R¹ may be identical or different from each other.

In another embodiment of the present invention, a compound of Formula(I′) wherein pyrazolyl is bonded to an amide structure at 3-position ispreferable. Moreover, a preferred embodiment of the compound of Formula(I′) wherein pyrazolyl is bonded to an amide structure at 3-position inpresent invention is

[22] a compound represented by Formula (II′) below or a salt thereof:

wherein R¹ ishalogen,cyano,substituted or unsubstituted C1-C6 alkyl,substituted or unsubstituted C3-C7 cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, ora substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur;R² issubstituted or unsubstituted C1-C10 alkyl,substituted or unsubstituted C3-C4 cycloalkyl,substituted or unsubstituted C2-C6 alkenyl, orsubstituted or unsubstituted C4-C12 bridged cycloalkyl;X isN orCR³, wherein R³ is

hydrogen,

halogen,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C2-C6 alkynyl, or

substituted or unsubstituted C1-C6 alkoxy; and

n is an integer of 1 to 3,

wherein when n is 2 or 3, R¹ may be identical or different from eachother.

In the present invention, the compound represented by Formula (II′)above is also referred to simply as Compound (II′).

[23] In Formula (II′),

R¹ is more preferably

halogen;

cyano;

C1-C6 alkyl that may be substituted with halogen or C1-C4 alkoxy;

C3-C7 cycloalkyl;

phenyl; or

a C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom;

R² is more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl that may be substituted with C1-C4 alkyl;X is more preferablyN orCR³, wherein R³ is

hydrogen;

halogen;

C1-C6 alkyl;

C2-C4 alkynyl that may be substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C10 monocyclic or polycyclic unsaturated        heterocyclic groups that may be substituted with C1-C6 alkyl and        contains 1 to 3 identical or different heteroatoms selected from        nitrogen, oxygen, and sulfur; or

C1-C4 alkoxy that may be substituted with one or more C3-C6 monocyclicsaturated heterocyclic groups containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and

n is more preferably 1 or 2,

wherein when n is 2, R¹ may be identical or different from each other.

[24] In Formula (II′),

R¹ is more preferably

halogen;

cyano;

C1-C6 alkyl that may be substituted with halogen;

C3-C7 cycloalkyl;

phenyl; or

a C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom;

R² is more preferably

linear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; orC4-C12 bridged cycloalkyl; andX is more preferablyN orCR³, wherein R³ is

hydrogen;

halogen;

C1-C4 alkyl,

C2-C4 alkynyl that may be substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy;    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C10 monocyclic or polycyclic unsaturated        heterocyclic groups that may be substituted with C1-C6 alkyl and        contains 1 to 3 identical or different heteroatoms selected from        nitrogen, oxygen, and sulfur; or

C1-C4 alkoxy; and

n is more preferably 1 or 2,

wherein when n is 2, R¹ may be identical or different from each other.

[25] In Formula (II′),

R¹ is more preferably

halogen,

cyano, or

C1-C4 alkyl that may be substituted with halogen;

R² is more preferably

linear C1-C4 alkyl that is substituted with C3-C7 cycloalkyl; branchedC3-C6 alkyl that may be substituted with halogen, C3-C7 cycloalkyl, oneor more C3-C6 monocyclic unsaturated heterocyclic groups containing onesulfur atom, or C1-C4 alkoxy;

C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl, orC3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with halogen; or

C4-C12 bridged cycloalkyl selected from bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl;

X is more preferably

N or

CR³, wherein R³ is

hydrogen; or

C2-C4 alkynyl that is substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C6 monocyclic unsaturated heterocyclic groups        that may be substituted with C1-C4 alkyl and contains 1 to 3        identical or different heteroatoms selected from nitrogen,        oxygen, and sulfur; and        n is more preferably an integer of 1.

Preferred in another embodiment of the present invention is

[26] a compound represented by Formula (IX′) below or a salt thereof:

wherein R¹ ishalogen;cyano;C1-C6 alkyl that may be substituted with halogen;C3-C7 cycloalkyl;phenyl; ora C3-C6 monocyclic unsaturated heterocyclic group containing one oxygenatom or one sulfur atom;R² islinear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom;C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl,halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; or C4-C12 bridgedcycloalkyl; andX isN orCR³, wherein R³ is

hydrogen;

halogen;

C1-C4 alkyl;

C2-C4 alkynyl that may be substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C10 monocyclic or polycyclic unsaturated        heterocyclic groups that may be substituted with C1-C6 alkyl and        contains 1 to 3 identical or different heteroatoms selected from        nitrogen, oxygen, and sulfur; or

C1-C4 alkoxy.

In the present invention, the compound represented by Formula (IX′)above is also referred to simply as Compound (IX′).

[27] In Formula (IX′),

R¹ is more preferably

halogen,

cyano, or

C1-C4 alkyl that may be substituted with halogen;

R² is more preferably

linear C1-C4 alkyl that is substituted with C3-C7 cycloalkyl;

branched C3-C6 alkyl that may be substituted with halogen, C3-C7cycloalkyl, one or more C3-C6 monocyclic unsaturated heterocyclic groupscontaining one sulfur atom, or C1-C4 alkoxy;

C3-C4 cycloalkyl that may be substituted with halogen, C1-C4 alkyl, orC3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with halogen; or

C4-C12 bridged cycloalkyl selected from bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl; and

X is more preferably

N or

CR³, wherein R³ is

hydrogen; or

C2-C4 alkynyl that is substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C6 monocyclic unsaturated heterocyclic groups        that may be substituted with C1-C4 alkyl and contains 1 to 3        identical or different heteroatoms selected from nitrogen,        oxygen, and sulfur.

[28] In Formula (IX′),

R¹ is more preferably

bromine,

cyano, or

C1-C4 alkyl that may be substituted with fluorine;

R² is more preferably

linear C1-C4 alkyl that is substituted with C3-C7 cycloalkyl; branchedC3-C6 alkyl that may be substituted with fluorine, C3-C7 cycloalkyl, oneor more C3-C6 monocyclic unsaturated heterocyclic groups containing onesulfur atom, or C1-C4 alkoxy;

C3-C4 cycloalkyl that may be substituted with fluorine, C1-C4 alkyl, orC3-C5 cycloalkyl;

C2-C6 alkenyl that may be substituted with fluorine; or

C4-C12 bridged cycloalkyl selected from bicyclo[1.1.1]pentan-1-yl andbicyclo[2.2.1]heptan-2-yl; and

X is more preferably

N or

CR³, wherein R³ is

hydrogen; or

C2-C4 alkynyl that is substituted with

-   -   C1-C6 alkyl that may be substituted with hydroxy,    -   C3-C7 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen, oxygen, and sulfur, or    -   one or more C3-C6 monocyclic unsaturated heterocyclic groups        that may be substituted with C1-C4 alkyl and contains 1 to 3        identical or different heteroatoms selected from nitrogen,        oxygen, and sulfur.

Moreover, in another embodiment of the present invention,

[29] in Formula (IX′),

R¹ is more preferably halogen or C1-C4 alkyl;

R² is more preferably

branched C3-C6 alkyl that may be substituted with halogen or C3-C5cycloalkyl,

C3-C4 cycloalkyl that may be substituted with C1-C4 alkyl, orbicyclo[2.2.1]heptan-2-yl; and

X is more preferably

N or

CR³, wherein R³ is

hydrogen; or

ethynyl or propynyl that is substituted with

-   -   C1-C4 alkyl that may be substituted with hydroxy,    -   C3-C5 cycloalkyl that may be substituted with hydroxy,    -   one or more C3-C6 monocyclic saturated heterocyclic groups        containing 1 to 3 identical or different heteroatoms selected        from nitrogen and oxygen, or    -   one or more C3-C6 monocyclic unsaturated heterocyclic groups        that may be substituted with methyl and contains 1 to 3 nitrogen        atoms.

[30] In Formula (IX′),

R¹ is more preferably bromine or methyl;

R² is more preferably

branched C3-C6 alkyl that may be substituted with fluorine or C3-C5cycloalkyl, or

C3-C4 cycloalkyl that may be substituted with methyl; and

X is more preferably

N or

CR³, wherein R³ is hydrogen.

[31] In Formula (IX′),

R¹ is more preferably methyl;

R² is more preferably

isopropyl or tert-butyl that may be substituted with fluorine orcyclopropyl, or

cyclopropyl that may be substituted with methyl; and

X is more preferably

N or

CR³, wherein R³ is hydrogen.

Moreover,

[32] in Formulas (I′), (II′), and (IX′) of the present invention, when Xis N,

R¹ is preferably

halogen,

cyano,

substituted or unsubstituted C1-C6 alkyl,

substituted or unsubstituted C3-C7 cycloalkyl,

substituted or unsubstituted C6-C14 aromatic hydrocarbon, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur; and

R² is preferably

substituted or unsubstituted C1-C10 alkyl,

substituted or unsubstituted C3-C4 cycloalkyl,

substituted or unsubstituted C2-C6 alkenyl, or

substituted or unsubstituted C4-C12 bridged cycloalkyl.

Moreover,

[33] in Formulas (I′), (II′), and (IX′) of the present invention, when Xis CR³ (R³ is as defined above),

R¹ is preferably

halogen,

substituted or unsubstituted C1-C6 alkyl, or

a substituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur; and

R² is preferably

substituted or unsubstituted C1-C10 alkyl,

substituted or unsubstituted C3-C4 cycloalkyl, or

substituted or unsubstituted C4-C12 bridged cycloalkyl.

Specific examples of the compound of the present invention include, butare not limited to, compounds produced in the Examples described later.

Specific preferred examples of Compound (I′) are as follows:

[34]

-   (11)    4-amino-1-cyclobutyl-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 11);-   (12)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-((1-methylcyclopropyl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 12);-   (13)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 13);-   (14)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 14);-   (15)    4-amino-1-(sec-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 15);-   (16)    4-amino-1-(cyclobutylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 16);-   (17)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 17);-   (18)    4-amino-1-(cyclopropylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 18);-   (19)    4-amino-1-(cyclopentylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 19);-   (20)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 20);-   (21)    4-amino-1-isopropyl-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 21);-   (22)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 22);-   (26)    4-amino-1-(3,3-dimethylcyclobutyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 26);-   (27)    4-amino-1-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 27);-   (28)    4-amino-1-(bicyclo[2.2.1]heptan-2-yl)-N-(5-bromo-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 28);-   (29)    1-(adamantan-2-yl)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 29);-   (30)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-((2S,3R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 30);-   (31)    4-amino-1-(3-fluoroprop-1-en-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 31);-   (34)    4-amino-1-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 34);-   (35)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 35);-   (36)    4-amino-1-(tert-butyl)-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 36);-   (37)    4-amino-1-(tert-butyl)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 37);-   (38)    4-amino-1-(tert-butyl)-N-(5-cyano-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 38);-   (39)    4-amino-1-(tert-butyl)-N-(5-ethyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 39);-   (40)    4-amino-1-(tert-butyl)-N-(5-isopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 40);-   (41)    4-amino-1-(tert-butyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 41);-   (42)    4-amino-1-(tert-butyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 42);-   (45)    4-amino-7-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 45);-   (46)    4-amino-7-(1-fluoropropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 46);-   (48)    4-amino-7-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 48);-   (49)    4-amino-7-(tert-butyl)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 49);-   (50)    4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 50);-   (51)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 51);-   (52)    4-amino-7-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 52);-   (53)    4-amino-7-(1-methoxy-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 53);-   (54)    4-amino-7-(1-(fluoromethyl)cyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 54);-   (55)    4-amino-7-(1-(difluoromethyl)cyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 55);-   (56)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2-(thiophen-2-yl)propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 56);-   (58)    4-amino-7-(bicyclo[1.1.1]pentan-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 58);-   (60)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2-phenylpropan-2-yl))-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 60);-   (61)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2,3,3-trimethylbutan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 61);-   (62)    4-amino-7-(2,3-dimethylbutan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 62);-   (63)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 63);-   (64)    4-amino-7-(tert-butyl)-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 64);-   (65)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 65);-   (66)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 66);-   (67)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 67);-   (68)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 68);-   (69)    4-amino-7-cyclobutyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 69);-   (70)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(tert-pentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 70);-   (71)    4-amino-7-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 71);-   (73)    4-amino-7-(tert-butyl)-6-methyl-N-(3-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 73);-   (74)    7-([1,1′-bi(cyclopropan)]-1-yl)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 74);-   (75)    4-amino-6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 75);-   (76)    4-amino-6-bromo-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 76);-   (77)    4-amino-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 77);-   (78)    4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 78);-   (79)    4-amino-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 79);-   (80)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 80);-   (81)    4-amino-6-((1-hydroxycyclopentyl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 81);-   (82)    4-amino-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 82);-   (83)    4-amino-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 83);-   (84)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(3-morpholino-1-propyn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 84);-   (85)    4-amino-6-(3-(1-hydroxycyclobutyl)-1-propyne)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 85);-   (86)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 86);-   (87)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-6-((1-methyl-1H-pyrazol-3-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 87);-   (88)    4-amino-6-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 88);-   (89)    4-amino-6-ethoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 89); and-   (90)    (R)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 90).

More preferred examples of Compound (I′) are as follows:

[35]

-   (27)    4-amino-1-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 27);-   (34)    4-amino-1-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 34);-   (45)    4-amino-7-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 45);-   (48)    4-amino-7-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 48);-   (50)    4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 50);-   (51)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 51);-   (52)    4-amino-7-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 52);-   (65)    4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 65);-   (68)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 68);-   (71)    4-amino-7-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 71);-   (79)    4-amino-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 79);-   (80)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 80);-   (81)    4-amino-6-((1-hydroxycyclopentyl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 81);-   (82)    4-amino-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 82);-   (83)    4-amino-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 83);-   (84)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(3-morpholino-1-propyn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 84); and-   (85)    4-amino-6-(3-(1-hydroxycyclobutyl)-1-propyne)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 85).

Even more preferred examples of Compound (I′) are as follows:

[36]

-   (34)    4-amino-1-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide    (example compound 34);-   (48)    4-amino-7-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 48);-   (50)    4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 50);-   (51)    4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 51); and-   (52)    4-amino-7-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide    (example compound 52).

Moreover, the present invention provides a RET inhibitor comprising thecompound or a salt thereof according to any one of [19] to [36] as anactive ingredient.

Moreover, the present invention provides a pharmaceutical compositioncomprising the compound or a salt thereof according to any one of [19]to [36].

Moreover, the present invention provides a pharmaceutical compositioncomprising the compound or a salt thereof according to any one of [19]to [36], wherein the pharmaceutical composition prevents or treats adisease that can be treated by RET inhibition.

Moreover, the present invention provides an antitumor agent comprisingthe compound or a salt thereof according to any one of [19] to [36].

Moreover, the present invention provides an antitumor agent comprisingthe compound or a salt thereof according to any one of [19] to [36],wherein the antitumor agent treats a malignant tumor with enhancedactivation of RET.

Moreover, the present invention provides the compound or a salt thereofaccording to any one of [19] to [36] for use in prevention or treatmentof a malignant tumor.

Moreover, the present invention provides the compound or a salt thereofaccording to any one of [19] to [36] for use in prevention or treatmentof a malignant tumor, wherein the malignant tumor is a malignant tumorwith enhanced activation of RET.

Moreover, the present invention provides use of the compound or a saltthereof according to any one of [19] to [36] for producing an antitumoragent.

Moreover, the present invention provides use of the compound or a saltthereof according to any one of [19] to [36] for producing an antitumoragent, wherein the antitumor agent is an antitumor agent for treating amalignant tumor with enhanced activation of RET.

Moreover, the present invention provides use of the compound or a saltthereof according to any one of [19] to [36] for producing a RETinhibitor.

Moreover, the present invention provides a method for preventing ortreating a malignant tumor, the method comprising administering thecompound or a salt thereof according to any one of [19] to [36] to amammal.

Moreover, the present invention provides a method for preventing ortreating a malignant tumor, the method comprising administering thecompound or a salt thereof according to any one of [19] to [36] to amammal, wherein the malignant tumor is a malignant tumor with enhancedactivation of RET.

Moreover, the present invention provides a method of inhibiting RETcomprising administering the compound or a salt thereof according to anyone of [19] to [36] to a mammal.

Next, the method for producing the compound of the present invention isdescribed.

Compound (I) of the present invention may be produced, for example,through the production methods below or the methods described in theExamples. Compound (I′) of the present invention may also be produced bythe same method for producing Compound (I). However, the method forproducing Compounds (I) and (I′) is not limited to these reactionexamples.

wherein L₁ is a leaving group, and R² and R³ are as defined above.Step 1

This step synthesizes a compound represented by Formula (BB) from acompound represented by Formula (AA).

Step 1 is performed using an amino compound represented by Formula (RE1)or a salt thereof in an amount of 0.5 to 5 moles, preferably 0.9 to 1.5moles, per mole of the compound represented by Formula (AA).

Examples of bases include inorganic bases, such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,cesium hydroxide, sodium hydride, and potassium hydride; and organicamines, such as trimethylamine, triethylamine, tripropylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, lutidine, and collidine. The amount ofthe base used is 1 to 100 moles, preferably 1 to 10 moles, per mole ofthe compound represented by Formula (AA). The amino compound can beobtained from commercial suppliers, or can be produced through a knownmethod. Moreover, the reaction can be promoted by adding an acid duringthe reaction, if necessary. Examples of acids include formic acid,acetic acid, hydrochloric acid, phosphoric acid, and the like. Theamount of the acid used is 1 to 100 moles, preferably 1 to 5 moles, permole of the compound represented by Formula (AA).

As the solvent used in the reaction, any solvent that does not adverselyaffect the reaction can be used. Examples of the solvent includealcohols (e.g., methanol and ethanol), hydrocarbons (e.g., benzene,toluene, and xylene), halogenated hydrocarbons (e.g., methylenechloride, chloroform, and 1,2-dichloroethane), nitriles (e.g.,acetonitrile), ethers (e.g., dimethoxyethane and tetrahydrofuran),aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide,and hexamethylphosphoramide), water, and mixtures thereof.

The reaction time ranges from 0.1 to 100 hours, preferably 0.5 to 48hours. The reaction temperature ranges from 0 to 120° C., preferably 50to 120° C.

The thus-obtained compound represented by Formula (BB) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

Step 2

This step synthesizes a compound represented by Formula (CC) from thecompound represented by Formula (BB).

Step 2 is performed using a halogenating reagent in an amount of 1 to 10moles, preferably 1 to 5 moles, per mole of the compound represented byFormula (BB).

Examples of halogenating reagents include N-iodosuccinimide,N-bromosuccinimide, N-chlorosuccinimide, iodine, bromine, and the like.The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include toluene, benzene, tetrahydrofuran, 1,4-dioxane,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide, and mixtures thereof.

Examples of the leaving group represented by L₁ include chlorine,bromine, iodine, and the like.

The reaction temperature generally ranges from −78 to 200° C.,preferably 0 to 50° C. The reaction time generally ranges from 5 minutesto 6 days, preferably 10 minutes to 3 days.

The thus-obtained compound represented by Formula (CC) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

Step 3

This step produces a compound represented by Formula (DD) by reactingthe compound represented by Formula (CC) with ammonia or a salt thereof.The amount of ammonia or a salt thereof used in this step is generallyan equimolar to excessive molar amount per mole of the compoundrepresented by Formula (CC).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include water, methanol, ethanol, isopropanol, tert-butylalcohol, tetrahydrofuran, 1,4-dioxane, dimethylformamide,N-methylpyrrolidone, 1,2-dimethoxyethane, dimethylsulfoxide, andmixtures thereof.

The reaction temperature generally ranges from 0 to 200° C., preferablyroom temperature to 150° C. The reaction time generally ranges from 5minutes to 7 days, preferably 30 minutes to 48 hours.

The thus-obtained compound represented by Formula (DD) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

wherein L₁ and L₂ are each a leaving group, and R² is as defined above.Step 4

This step produces a compound represented by Formula (FF) using acompound represented by Formula (EE) and a compound represented byFormula (III) or (IV).

When the compound represented by Formula (III) is used as an alkylatingreagent, the compound represented by Formula (FF) can be produced in thepresence of a base. In Formula (III), L₂ is a leaving group such aschlorine, bromine, iodine, methanesulfonic acid ester, orp-toluenesulfonic acid ester; and can be obtained from commercialsuppliers, or can be produced through a known method. The amount of thecompound represented by Formula (III) used is 1 to 10 moles, preferably1 to 5 moles, per mole of the compound represented by Formula (EE).

Examples of bases include inorganic bases, such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,cesium hydroxide, sodium hydride, and potassium hydride; and organicamines, such as trimethylamine, triethylamine, tripropylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, lutidine, and collidine. The amount ofthe base used is 1 to 100 moles, preferably 2 to 10 moles, per mole ofthe compound represented by Formula (EE).

Examples of the solvent include N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane,N-methylpyrrolidin-2-one, acetonitrile, and the like. These solvents maybe used alone or in a mixture.

The reaction time ranges from 0.1 to 100 hours, preferably 0.5 to 24hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0 to 100° C.

When the compound of Formula (IV) is used as an alkylating reagent, thecompound represented by Formula (FF) can be produced through a Mitsunobureaction. This step can generally be performed by a known method, forexample, the method disclosed in Chemical Reviews, Vol. 109, p. 2551(2009). For example, this step can be performed in the presence of aMitsunobu reagent and a phosphine reagent in a solvent that does notadversely affect the reaction. This step is generally performed usingthe compound represented by Formula (IV) in an amount of 1 to 10 moles,preferably 1 to 5 moles, per mole of the compound represented by Formula(EE).

Examples of Mitsunobu reagents include diethyl azodicarboxylate,diisopropyl azodicarboxylate, and the like. The amount of the Mitsunobureagent used is 1 to 10 moles, preferably 1 to 5 moles, per mole of thecompound represented by Formula (EE).

Examples of phosphine reagents include triphenylphosphine andtributylphosphine. The amount of the phosphine reagent used is 1 to 10moles, preferably 1 to 5 moles, per mole of the compound represented byFormula (EE).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include toluene, benzene, tetrahydrofuran, 1,4-dioxane,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide, and mixtures thereof.

The reaction temperature generally ranges from −78 to 200° C.,preferably 0 to 50° C. The reaction time generally ranges from 5 minutesto 3 days, preferably 10 minutes to 10 hours.

The thus-obtained compound represented by Formula (FF) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

Step 5

This step produces a compound represented by Formula (GG) by reactingthe compound represented by Formula (FF) with ammonia or a salt thereof.The amount of ammonia or a salt thereof used in this step is generallyan equimolar to excessive molar amount per mole of the compoundrepresented by Formula (FF).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include water, methanol, ethanol, isopropanol, tert-butylalcohol, tetrahydrofuran, 1,4-dioxane, dimethylformamide,1,2-dimethoxyethane, N-methylpyrrolidone, dimethylsulfoxide, andmixtures thereof.

The reaction temperature generally ranges from 0 to 200° C., preferablyroom temperature to 150° C. The reaction time generally ranges from 5minutes to 7 days, preferably 30 minutes to 24 hours.

The thus-obtained compound represented by Formula (GG) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

wherein L₁ and L₂ are each a leaving group, and R² is as defined above.Step 6

This step produces a compound represented by Formula (WW) using acompound represented by Formula (QQ) and a compound represented byFormula (III) or (IV).

When the compound represented by Formula (III) is used as an alkylatingreagent, the compound represented by Formula (WW) can be produced in thepresence of a base. In Formula (III), L₂ is a leaving group such aschlorine, bromine, iodine, methanesulfonic acid ester, orp-toluenesulfonic acid ester; and can be obtained from commercialsuppliers, or can be produced through a known method. The amount of thecompound represented by Formula (III) used is 1 to 10 moles, preferably1 to 5 moles, per mole of the compound represented by Formula (QQ).

Examples of bases include inorganic bases, such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate,cesium hydroxide, sodium hydride, and potassium hydride; and organicamines, such as trimethylamine, triethylamine, tripropylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, lutidine, and collidine. The amount ofthe base used is 1 to 100 moles, preferably 2 to 10 moles, per mole ofthe compound represented by Formula (QQ). Examples of the solventinclude N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile,and the like. These solvents may be used alone or in a mixture.

The reaction time ranges from 0.1 to 100 hours, preferably 0.5 to 24hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0 to 100° C.

When the compound of Formula (IV) is used as an alkylating reagent, thecompound represented by Formula (WW) can be produced through a Mitsunobureaction. This step can generally be performed by a known method, forexample, the method disclosed in Chemical Reviews, Vol. 109, p. 2551(2009). For example, this step can be performed in the presence of aMitsunobu reagent and a phosphine reagent in a solvent that does notadversely affect the reaction. This step is generally performed usingthe compound represented by Formula (IV) in an amount of 1 to 10 moles,preferably 1 to 5 moles, per mole of the compound represented by Formula(QQ).

Examples of Mitsunobu reagents include diethyl azodicarboxylate,diisopropyl azodicarboxylate, and the like. The amount of the Mitsunobureagent used is 1 to 10 moles, preferably 1 to 5 moles, per mole of thecompound represented by Formula (QQ). Examples of phosphine reagentsinclude triphenylphosphine and tributylphosphine. The amount of thephosphine reagent used is 1 to 10 moles, preferably 1 to 5 moles, permole of the compound represented by Formula (QQ).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include toluene, benzene, tetrahydrofuran, 1,4-dioxane,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide, and mixtures thereof.

The reaction temperature generally ranges from −78 to 200° C.,preferably 0 to 50° C. The reaction time generally ranges from 5 minutesto 3 days, preferably 10 minutes to 10 hours.

The thus-obtained compound represented by Formula (WW) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

wherein L₁ is a leaving group, and R² and X are as defined above.Step 7

This step produces a compound represented by Formula (JJ) by reacting acompound represented by Formula (HH) in a carbon monoxide atmosphere inthe presence of an alcohol using, for example, a transition metal andoptionally a base in a solvent that does not adversely affect thereaction.

The compound represented by Formula (HH) can be produced by steps 1 to3, steps 4 and 5, or step 6 of the production method of the presentapplication.

In this step, the pressure of carbon monoxide is generally 1 atm to 10atms, preferably 1 atm to 7 atms.

The amount of the alcohol compound used is 1 to an excessive molaramount, preferably 1 to 200 moles, per mole of the compound representedby Formula (HH). Examples of alcohol compounds include methanol,ethanol, propanol, isopropyl alcohol, diethylaminoethanol, isobutanol,4-(2-hydroxyethyl)morpholine, 3-morpholinopropanol,diethylaminopropanol, and the like.

Examples of transition metal catalysts usable in this step includepalladium catalysts (e.g., palladium acetate,tris(benzylideneacetone)dipalladium,bis(triphenylphosphine)palladium(II) dichloride,1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, carbon-supported palladium, etc.).As necessary, a ligand (e.g., triphenylphosphine, xantphos,tri-tert-butylphosphine, etc.) is added. The amount of the transitionmetal catalyst varies depending on the type of catalyst. For example,the amount of the transition metal catalyst used is generally 0.0001 to1 mole, preferably 0.001 to 0.5 moles, per mole of the compoundrepresented by Formula (HH). The amount of the ligand used is generally0.000 1 to 4 moles, preferably 0.01 to 2 moles, per mole of the compoundrepresented by Formula (HH).

Further, a base may be added during the above reaction as necessary.Examples of bases include organic bases, such as triethylamine,diisopropylethylamine, pyridine, lutidine, collidine,4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate,sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and butyllithium; and inorganic bases, such assodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydroxide, and sodium hydride. The amount of the baseused is generally 0.1 to 50 moles, preferably 1 to 20 moles, per mole ofthe compound represented by Formula (HH).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include hydrocarbons (e.g., benzene, toluene, and xylene),nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol andethanol), aprotic polar solvents (e.g., dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, andhexamethylphosphoramide), water, and mixtures thereof. The reaction timeranges from 0.1 to 100 hours, preferably 0.5 to 24 hours. The reactiontemperature is 0° C. to 200° C., preferably 0 to 150° C.

When a mixture of an ester form corresponding to the alcohol used and acarboxylic acid compound (JJ) is obtained after this reaction, ahydrolysis reaction can be performed to convert the mixture into acompound represented by Formula (JJ). Hydrolysis is performed using abase. Examples of bases include organic bases, such as diethylamine,diisopropylamine, potassium tert-butyrate, sodium tert-butyrate, sodiummethoxide, sodium ethoxide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium;and inorganic bases, such as sodium hydrogen carbonate, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydroxide,potassium hydroxide, lithium hydroxide, and calcium hydroxide.

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include hydrocarbons (e.g., benzene, toluene, and xylene),nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol andethanol), aprotic polar solvents (e.g., dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, andhexamethylphosphoramide), water, and mixtures thereof.

The reaction time ranges from 0.1 to 100 hours, preferably 0.5 to 24hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0 to 150° C.

The thus-obtained compound represented by Formula (JJ) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

wherein L₁ is a leaving group; E is ester, cyano, or carboxylic acidequivalent, such as carboxamide; Z is halogen; and R² and R³ are asdefined above.Step 8 This step produces an ester derivative or cyano derivativerepresented by Formula (KK) by reacting the compound represented byFormula (GG), in a carbon monoxide atmosphere in the presence of analcohol, or using a cyano compound, such as copper cyanide or zinccyanide, using, for example, a transition metal catalyst and optionallya base in a solvent that does not adversely affect the reaction.

The compound represented by Formula (GG) can be produced by steps 1 to3, steps 4 and 5 of the production method of the present application.

In the production of the ester derivative, the pressure of carbonmonoxide is generally 1 atm to 10 atms, preferably 1 atm to 7 atms. Theamount of the alcohol compound used as a reaction agent is 1 to anexcessive molar amount, preferably 1 to 200 moles, per mole of thecompound represented by Formula (GG). Examples of alcohol compoundsinclude methanol, ethanol, propanol, isopropyl alcohol,diethylaminoethanol, isobutanol, 4-(2-hydroxyethyl) morpholine,3-morpholinopropanol, diethylaminopropanol, and the like.

In the production of the cyano derivative, examples of the cyanocompound used as a reaction agent include copper cyanide, zinc cyanide,tri-n-butylcyanotin, and the like. The amount of the cyano compound usedas an agent is generally 1 to 100 moles, preferably 1 to 10 moles, permole of the compound represented by Formula (GG).

Examples of transition metal catalysts usable in this step for both theproduction of the ester derivative and the production of the cyanoderivative include palladium catalysts (e.g., palladium acetate,tetrakis triphenylphosphine palladium,tris(benzylideneacetone)dipalladium,bis(triphenylphosphine)palladium(II) dichloride,1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, carbon-supported palladium, etc.).As necessary, a ligand (e.g., triphenylphosphine, xantphos,tri-tert-butylphosphine, etc.) is added. The amount of the transitionmetal catalyst varies depending on the type of catalyst. For example,the amount of the transition metal catalyst used is generally 0.0001 to1 mole, preferably 0.001 to 0.5 moles, per mole of the compoundrepresented by Formula (GG). The amount of the ligand used is generally0.000 1 to 4 moles, preferably 0.01 to 2 moles, per mole of the compoundrepresented by Formula (GG).

Further, a base may be added during the above reaction as necessary.Examples of bases include organic bases, such as triethylamine,diisopropylethylamine, pyridine, lutidine, collidine,4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate,sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and butyllithium; and inorganic bases, such assodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydroxide, and sodium hydride. The amount of the baseused is generally 0.1 to 50 moles, preferably 1 to 20 moles, per mole ofthe compound represented by Formula (GG).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include hydrocarbons (e.g., benzene, toluene, and xylene),nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol andethanol), aprotic polar solvents (e.g., dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, andhexamethylphosphoramide), water, and mixtures thereof. The reaction timeranges from 0.1 to 100 hours, preferably 0.5 to 24 hours. The reactiontemperature is 0° C. to 200° C., preferably 0 to 150° C. Thethus-obtained compound represented by Formula (KK) can be subjected tothe subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

Step 9

This step produces a halogen compound (LL) by treating the compoundrepresented by Formula (KK) with a halogenating agent.

This step is generally performed using a halogenated reagent in anamount of 1 to 10 moles, preferably 1 to 5 moles, per mole of thecompound represented by Formula (KK).

Examples of halogenating reagents include1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), N-iodosuccinimide, N-bromosuccinimide,N-chlorosuccinimide, iodine, bromine, and the like. The reaction solventis not particularly limited, and any solvent that does not adverselyaffect the reaction can be used. Examples of the solvent includedichloromethane, chloroform, toluene, benzene, tetrahydrofuran,1,4-dioxane, dimethylformamide, dimethylacetamide,N-methylpyrrolidinone, dimethylsulfoxide, and mixtures thereof.

Examples of the halogen represented by Z include fluorine, chlorine,bromine, iodine, and the like.

The reaction temperature generally ranges from −78 to 200° C.,preferably 0 to 50° C. The reaction time generally ranges from 5 minutesto 6 days, preferably 10 minutes to 3 days.

The thus-obtained compound represented by Formula (LL) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

Moreover, E can be converted to another E, as required, by a knownmethod, such as hydrolysis or solvolysis. For example, cyano can beconverted to carboxamide by hydrolysis, and cyano or carboxamide can beconverted to ester by solvolysis.

Step 10

This step produces a compound represented by Formula (MM) by subjectingthe compound represented by Formula (LL) to a coupling reaction with aborate derivative, boric acid derivative, tin derivative, acetylenederivative, or alkoxide derivative that has R³ using, for example, atransition metal and optionally a base in a solvent that does notadversely affect the reaction.

The amount of the borate derivative, boric acid derivative, tinderivative, acetylene derivative, or alkoxide derivative that has R³used is 1 to 100 moles, preferably 1 to 20 moles. Examples of transitionmetal catalysts usable in this step include palladium catalysts (e.g.,palladium acetate, tetrakis triphenylphosphine palladium,tris(benzylideneacetone)dipalladium,bis(triphenylphosphine)palladium(II) dichloride,1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, etc.). As necessary, a ligand (e.g.,triphenylphosphine, xantphos,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, tricyclohexylphosphine,tri-tert-butylphosphine, etc.) is added. Examples of copper catalystsinclude copper iodide, copper bromide, and copper chloride. The amountof the transition metal catalyst varies depending on the type ofcatalyst. For example, the amount of the transition metal catalyst usedis generally 0.0001 to 1 mole, preferably 0.001 to 0.5 moles, per moleof the compound represented by Formula (LL). Transition metal catalystscan be used in combination, as necessary. The amount of the ligand usedis generally 0.000 1 to 4 moles, preferably 0.01 to 2 moles, per mole ofthe compound represented by Formula (LL).

Further, a base may be added during the above reaction as necessary.Examples of bases include organic bases, such as triethylamine,diisopropylethylamine, pyridine, lutidine, collidine,4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate,sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and butyllithium; and inorganic bases, such assodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, potassium phosphate, sodium hydroxide, and sodium hydride.The amount of the base used is generally 0.1 to 50 moles, preferably 1to 20 moles, per mole of the compound represented by Formula (LL).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include hydrocarbons (e.g., benzene, toluene, and xylene),nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol, ethanol,and ethylene glycol), aprotic polar solvents (e.g., dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, andhexamethylphosphoramide), water, and mixtures thereof.

The reaction time ranges from 0.1 to 100 hours, preferably 0.5 to 24hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0 to 160° C. Moreover, thereaction can be performed while appropriately protecting the compoundrepresented by Formula (LL) with a protecting group, such as Boc(tert-butoxycarbonyl), and then the protecting group can be removed.

The thus-obtained compound represented by Formula (MM) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

wherein E, R², and R³ are as defined above.Step 11

This step produces a carboxylic acid compound represented by Formula(NN) by hydrolyzing the compound represented by Formula (MM).

Hydrolysis is performed using a base or an acid. Examples of basesinclude organic bases, such as diethylamine, diisopropylamine, potassiumtert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide,lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and butyllithium; and inorganic bases, such assodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, andcalcium hydroxide. Examples of acids include hydrochloric acid, sulfuricacid, phosphoric acid, and the like.

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include hydrocarbons (e.g., benzene, toluene, and xylene),nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol, ethanol,and ethylene glycol), aprotic polar solvents (e.g., dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, andhexamethylphosphoramide), water, and mixtures thereof.

The reaction time ranges from 0.1 to 100 hours, preferably 0.5 to 24hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0 to 160° C.

The thus-obtained compound represented by Formula (NN) can be subjectedto the subsequent step after, or without, isolation and purification byknown separation and purification means, such as concentration, vacuumconcentration, crystallization, solvent extraction, reprecipitation, andchromatography.

wherein A, R², and X are as defined above.Step 12

This step produces a compound represented by Formula (I) by performingan amidation reaction using the compound represented by Formula (JJ) anda compound represented by Formula (VII). This step is performed in thepresence of an appropriate condensing agent or activating agent as anamidation reagent, using the compound of Formula (VII) in an amount of0.5 to 10 moles, preferably 1 to 3 moles, per mole of the compoundrepresented by Formula (JJ).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include isopropanol, tert-butyl alcohol, toluene, benzene,methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide, acetonitrile, and mixtures thereof.

The reaction temperature generally ranges from −78 to 200° C.,preferably 0 to 100° C. The reaction time generally ranges from 5minutes to 7 days, preferably 5 minutes to 3 days, more preferably 5minutes to 1 day.

Examples of condensing agents and activating agents includediphenylphosphoryl azide, N,N′-dicyclohexylcarbodiimide,benzotriazol-1-yloxy-trisdimethylaminophosphonium salt,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, combination of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and1-hydroxybenzotriazole, 2-chloro-1,3-dimethylimidazolinium chloride,(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminiumhexafluorophosphate, 1,1-carbonyldiimidazole, N-hydroxysuccinic acidimide, and the like.

Further, a base may be added during the above reaction as necessary.Examples of bases include organic bases, such as triethylamine,diisopropylethylamine, pyridine, lutidine, collidine,4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate,sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, potassium hexamethyldisilazide,diazabicycloundecene, diazabicyclononene, and butyllithium; andinorganic bases, such as sodium hydrogen carbonate, sodium carbonate,potassium carbonate, cesium carbonate, sodium hydroxide, and sodiumhydride. The amount of the base added is 1 to 100 moles, preferably 1 to10 moles, per mole of the compound represented by Formula (JJ).

After completion of the reaction, a base, such as a sodium hydroxidesolution, can be added to perform a post-treatment.

The thus-obtained compound represented by Formula (I) can be isolatedand purified by known separation and purification means, such asconcentration, vacuum concentration, crystallization, solventextraction, reprecipitation, and chromatography.

wherein L₁ is a leaving group, and A, R², and X are as defined above.Step 13

This step produces a compound represented by Formula (I) by reacting thecompound represented by Formula (HH) in the presence of Compound (VII)in a carbon monoxide atmosphere using, for example, a transition metaland optionally a base in a solvent that does not adversely affect thereaction.

In this step, the pressure of carbon monoxide is 1 atm to 10 atms,preferably 1 atm to 7 atms.

Examples of transition metal catalysts usable in this step includepalladium catalysts (e.g., palladium acetate,tris(dibenzylideneacetone)dipalladium,bis(triphenylphosphine)palladium(II) dichloride,1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, carbon-supported palladium, etc.).As necessary, a ligand (e.g., triphenylphosphine, xantphos,tri-tert-butylphosphine, etc.) is added. The amount of the transitionmetal catalyst varies depending on the type of catalyst. For example,the amount of the transition metal catalyst used is generally 0.0001 to1 mole, preferably 0.001 to 0.5 moles, per mole of the compoundrepresented by Formula (HH). The amount of the ligand used is generally0.000 1 to 4 moles, preferably 0.01 to 2 moles, per mole of the compoundrepresented by Formula (HH).

Further, a base may be added during the above reaction as necessary.Examples of bases include organic bases, such as triethylamine,diisopropylethylamine, pyridine, lutidine, collidine,4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate,sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide,1,8-diazabicyclo[5.4.0]undec-7-ene, potassium hexamethyldisilazide, andbutyllithium; and inorganic bases, such as sodium hydrogen carbonate,sodium carbonate, potassium carbonate, cesium carbonate, sodiumhydroxide, and sodium hydride. The amount of the base used is generally0.1 to 50 moles, preferably 1 to 20 moles, per mole of the compoundrepresented by Formula (HH).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include hydrocarbons (e.g., benzene, toluene, and xylene),nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol andethanol), aprotic polar solvents (e.g., dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, andhexamethylphosphoramide), water, and mixtures thereof. The reaction timeranges from 0.1 to 100 hours, preferably 0.5 to 24 hours. The reactiontemperature is 0° C. to 250° C., preferably 0 to 200° C.

The thus-obtained compound represented by Formula (I) can be isolatedand purified by known separation and purification means, such asconcentration, vacuum concentration, crystallization, solventextraction, reprecipitation, and chromatography.

wherein A, R², and R³ are as defined above.

This step produces a compound represented by Formula (SS) by subjectinga compound represented by Formula (RR) to a coupling reaction with aborate derivative, boric acid derivative, tin derivative, or acetylenederivative that has R³ using, for example, a transition metal andoptionally a base in a solvent that does not adversely affect thereaction.

The amount of the borate derivative, boric acid derivative, tinderivative, or acetylene derivative that has R³ used is 1 to 100 moles,preferably 1 to 20 moles. Examples of transition metal catalysts usablein this step include palladium catalysts (e.g., palladium acetate,tetrakis triphenylphosphine palladium,tris(benzylideneacetone)dipalladium,bis(triphenylphosphine)palladium(II) dichloride,1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, etc.). As necessary, a ligand (e.g.,triphenylphosphine, xantphos,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, tricyclohexylphosphine,tri-tert-butylphosphine, etc.) is added. Examples of copper catalystsinclude copper iodide, copper bromide, and copper chloride. The amountof the transition metal catalyst varies depending on the type ofcatalyst. For example, the amount of the transition metal catalyst usedis generally 0.0001 to 1 mole, preferably 0.001 to 0.5 moles, per moleof the compound represented by Formula (RR). Transition metal catalystscan be used in combination, as necessary. The amount of the ligand usedis generally 0.000 1 to 4 moles, preferably 0.01 to 2 moles, per mole ofthe compound represented by Formula (RR).

Further, a base may be added during the above reaction as necessary.Examples of bases include organic bases, such as triethylamine,diisopropylethylamine, pyridine, lutidine, collidine,4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate,sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, and butyllithium; and inorganic bases, such assodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, potassium phosphate, sodium hydroxide, and sodium hydride.The amount of the base used is generally 0.1 to 50 moles, preferably 1to 20 moles, per mole of the compound represented by Formula (RR).

The reaction solvent is not particularly limited, and any solvent thatdoes not adversely affect the reaction can be used. Examples of thesolvent include hydrocarbons (e.g., benzene, toluene, and xylene),nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane,tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol, ethanol,and ethylene glycol), aprotic polar solvents (e.g., dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, andhexamethylphosphoramide), water, and mixtures thereof.

The reaction time ranges from 0.1 to 100 hours, preferably 0.5 to 24hours. The reaction temperature ranges from 0° C. to the boilingtemperature of the solvent, preferably 0 to 160° C.

The thus-obtained compound represented by Formula (SS) can be isolatedand purified by known separation and purification means, such asconcentration, vacuum concentration, crystallization, solventextraction, reprecipitation, and chromatography.

When the compound of the present invention has isomers, such as opticalisomers, stereoisomers, regioisomers, and rotational isomers, mixturesof any of the isomers are included within the scope of the compound ofthe present invention. For example, when the compound of the presentinvention has optical isomers, the optical isomer separated from aracemic mixture is also included within the scope of the compound of thepresent invention. Each of such isomers can be obtained as a singlecompound by known synthesis and separation means (e.g., concentration,solvent extraction, column chromatography, recrystallization, etc.).

The compound or a salt thereof of the present invention may be in theform of crystals. Single crystals and polymorphic mixtures are includedwithin the scope of the compound or a salt thereof of the presentinvention. Such crystals can be produced by crystallization according toa crystallization method known per se in the art. The compound or a saltthereof of the present invention may be a solvate (e.g., a hydrate) or anon-solvate. Any of such forms are included within the scope of thecompound or a salt thereof of the present invention. Compounds labeledwith an isotope (e.g., ²H, ³H, ¹³C, ¹⁴C, ³⁵S, ¹²⁵I, etc.) are alsoincluded within the scope of the compound or a salt thereof of thepresent invention.

A prodrug of the compound or a salt thereof of the present inventionrefers to a compound that can be converted to the compound or a saltthereof of the present invention through a reaction with an enzyme,gastric acid, or the like, under physiological conditions in vivo, i.e.,a compound that can be converted to the compound or a salt thereof ofthe present invention by enzymatic oxidation, reduction, hydrolysis, orthe like; or a compound that can be converted to the compound or a saltthereof of the present invention by hydrolysis with gastric acid or thelike. Further, the prodrug of the compound or a salt thereof of thepresent invention may be compounds that can be converted to the compoundor a salt thereof of the present invention under physiologicalconditions, such as those described in “Iyakuhin no Kaihatsu[Development of Pharmaceuticals],” Vol. 7, Molecular Design, publishedin 1990 by Hirokawa Shoten Co., pp. 163-198.

The salt of the compound of the present invention refers to a commonsalt used in the field of organic chemistry. Examples of such saltsinclude base addition salts to a carboxyl group when the compound has acarboxyl group, and acid addition salts to an amino or basicheterocyclic group when the compound has an amino or basic heterocyclicgroup.

Examples of base addition salts include alkali metal salts such assodium salts and potassium salts; alkaline earth metal salts such ascalcium salts and magnesium salts; ammonium salts; and organic aminesalts such as trimethylamine salts, triethylamine salts,dicyclohexylamine salts, ethanolamine salts, diethanolamine salts,triethanolamine salts, procaine salts, and N,N′-dibenzylethylenediaminesalts.

Examples of acid addition salts include inorganic acid salts such ashydrochloride, sulfate, nitrate, phosphate, and perchlorate; organicacid salts such as acetate, formate, maleate, fumarate, tartrate,citrate, ascorbate, and trifluoroacetate; and sulfonates such asmethanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.

The compound or a salt thereof of the present invention has superior RETinhibitory activity and is useful as an antitumor agent. Preferableantitumor agents are antitumor agents for treating malignant tumors withenhanced activation of RET. The compound or a salt thereof of thepresent invention has excellent RET selectivity and has the advantagethat there are few side effects caused by inhibition of other kinases.

In the present specification, “RET” means RET (rearranged duringtransfection) tyrosine kinase, and includes human RET and non-humanmammal RET, preferably human RET. Further, the term “RET” includesisoforms.

Moreover, due to their excellent RET inhibitory activity, the compoundor a salt thereof of the present invention is useful as a pharmaceuticalpreparation for preventing and treating RET-related diseases. Examplesof the “RET-related diseases” include diseases whose incidence can bereduced, and whose symptom can be remitted, relieved, and/or completelycured by deleting, suppressing, and/or inhibiting the function of RET.The “RET-related diseases” are preferably diseases that can be treatedby RET inhibition. Examples of such diseases include, but not limitedto, malignant tumors, etc. Examples of the malignant tumor include thosewith enhanced activation of RET. The malignant tumor with enhancedactivation of RET refers a malignant tumor with enhanced activation ofRET due to the translocation, mutation (including point mutation andgene fusion mutation), and overexpression (including states in which thenumber of copies of the RET gene increases, the messenger RNA of RET isoverexpressed, the number of RET proteins increases, and the RETproteins are constantly activated) of the RET gene.

The type of malignant tumor to be treated by the compound or a saltthereof of the present invention is not particularly limited. Examplesof malignant tumors include epithelial cancers (respiratory systemcancers, digestive system cancers, reproductive system cancers,secretion system cancers, etc.), sarcomas, hematopoietic tumors, centralnervous system tumors, and peripheral nerve tumors.

Specific examples of the type of cancer include head and neck cancer,thyroid cancer, esophagus cancer, gastric cancer, duodenal cancer, livercancer, biliary tract cancer (gallbladder, cholangiocarcinoma, etc.),pancreas cancer, colorectal cancer (colon cancer, rectal cancer, etc.),lung cancer (non-small cell lung cancer, small cell lung cancer,mesothelioma, etc.), breast cancer, ovarian cancer, uterine cancer(cervical cancer, endometrial cancer, etc.), renal cancer, renalpelvis-ureteral cancer, bladder cancer, prostate cancer, testiculartumor, leukemia, malignant lymphoma, multiple myeloma, osteosarcoma,soft-tissue sarcoma, skin cancer, brain tumor, adrenal tumor,neuroblastoma, and the like.

The target cancer is preferably lung cancer (non-small cell lung cancer,small cell lung cancer, mesothelioma, etc.), colorectal cancer (coloncancer, rectal cancer, etc.), thyroid cancer, breast cancer, braintumor, and leukemia; more preferably non-small cell lung cancer andthyroid cancer; and more preferably non-small cell lung cancer andthyroid cancer with enhanced activation of RET. The meaning of thephrase “enhanced activation of RET” is as defined above.

The pharmaceutical composition comprising the compound or a salt thereofof the present invention is preferably a pharmaceutical composition forpreventing or treating diseases that can be treated by RET inhibition.Preferable pharmaceutical compositions are antitumor agents. When thecompound or a salt thereof of the present invention is used as apharmaceutical preparation, a pharmaceutical carrier can be added, ifrequired, thereby forming a suitable dosage form according to preventionand treatment purposes. Examples of the dosage form include oralpreparations, injections, suppositories, ointments, patches, and thelike. Such dosage forms can be formed by methods conventionally known topersons skilled in the art.

As the pharmaceutical carrier, various conventional organic or inorganiccarrier materials used as preparation materials may be blended as anexcipient, binder, disintegrant, lubricant, or coating agent in solidpreparations; or as a solvent, solubilizing agent, suspending agent,isotonizing agent, pH adjuster/buffer, or soothing agent in liquidpreparations. Moreover, pharmaceutical preparation additives, such asantiseptics, antioxidants, colorants, sweeteners, and stabilizers, mayalso be used, if required.

Examples of excipients include lactose, sucrose, D-mannitol, starch,crystalline cellulose, calcium silicate, and the like.

Examples of binders include hydroxypropyl cellulose, methyl cellulose,polyvinylpyrrolidone, candy powder, hypromellose, and the like.

Examples of disintegrants include sodium starch glycolate, carmellosecalcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and the like.

Examples of lubricants include talc, magnesium stearate, sucrose fattyacid ester, stearic acid, sodium stearyl fumarate, and the like.

Examples of coating agents include ethyl cellulose, aminoalkylmethacrylate copolymer RS, hypromellose, sucrose, and the like.

Examples of solvents include water, propylene glycol, physiologicalsaline, and the like.

Examples of solubilizing agents include polyethylene glycol, ethanol,α-cyclodextrin, macrogol 400, polysorbate 80, and the like.

Examples of suspending agents include carrageenan, crystallinecellulose/carmellose sodium, polyoxyethylene hydrogenated castor oil,and the like.

Examples of isotonizing agents include sodium chloride, glycerin,potassium chloride, and the like.

Examples of pH adjusters/buffers include sodium citrate, hydrochloricacid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, and thelike.

Examples of soothing agents include procaine hydrochloride, lidocaine,and the like.

Examples of antiseptics include ethyl parahydroxybenzoate, cresol,benzalkonium chloride, and the like.

Examples of antioxidants include sodium sulfite, ascorbic acid, naturalvitamin E, and the like.

Examples of colorants include titanium oxide, iron sesquioxide, FoodBlue No. 1, copper chlorophyll, and the like.

Examples of sweeteners include aspartame, saccharin, sucralose,l-menthol, mint flavor, and the like.

Examples of stabilizers include sodium pyrosulfite, disodium edetate,erythorbic acid, magnesium oxide, dibutylhydroxytoluene, and the like.

When a solid preparation for oral administration is prepared, anexcipient, optionally an excipient, a binder, a disintegrator, alubricant, a colorant, a sweetener, and the like, may be added to thecompound of the present invention; and the resulting mixture may beformulated into tablets, coated tablets, granules, powders, capsules,etc., according to an ordinary method.

When an injection is prepared, a pH adjuster, a buffer, a stabilizer, anisotonizing agent, a local anesthetic, and the like may be added to thecompound of the present invention; and the resulting mixture may beformulated into subcutaneous, intramuscular, and intravenous injectionsaccording to an ordinary method.

The amount of the compound of the present invention to be incorporatedin each of such dosage unit forms depends on the condition of thepatient to whom the compound is administered, the dosage form, etc. Ingeneral, in the case of an oral agent, an injection, and a suppository,the amount of the compound of the present invention is preferably 0.05to 1000 mg, 0.01 to 500 mg, and 1 to 1000 mg, respectively, per dosageunit form.

The daily dose of the medicine in such a dosage form depends on thecondition, body weight, age, gender, etc., of the patient, and cannot begeneralized. For example, the daily dose of the compound of the presentinvention for an adult (body weight: 50 kg) may be generally 0.05 to5000 mg, and preferably 0.1 to 1000 mg; and is preferably administeredin one dose, or in two to three divided doses, per day.

In the present invention, examples of mammals to which Compound (I) or asalt thereof is administered include humans, monkeys, mice, rats,rabbits, dogs, cats, cows, horses, pigs, sheep, and the like.

EXAMPLES

The following describes the present invention in more detail withreference to Examples. However, the present invention is not limited tothe Examples.

Commercially available reagents were used in the Examples, unlessotherwise specified. For silica gel column chromatography, the followingcolumns were used: Purif-Pack (registered trademark) SI produced byMoritex Corp., KP-Sil (registered trademark) silica prepacked columnproduced by Biotage, HP-Sphere (registered trademark) silica prepackedcolumn produced by Biotage, or HP-Sil (registered trademark) silicaprepacked column produced by Biotage. For basic silica gel columnchromatography, a Purif-Pack (registered trademark) NH produced byMoritex Corp. or KP-NH (registered trademark) prepacked column producedby Biotage was used. For preparative thin-layer chromatography,Kieselgel TM 60F 254, Art. 5744 produced by Merck or an NH₂ Silica Gel60F254 Plate produced by Wako was used. NMR spectra were measured byusing an AL400 (400 MHz; produced by JEOL), Mercury 400 (400 MHz;produced by Agilent Technologies, Inc.) model spectrometer, or Inova 400(400 MHz; produced by Agilent Technologies, Inc.) model spectrometerequipped with an OMNMR probe (Protasis). The measurement was carried outusing tetramethylsilane as an internal standard when tetramethylsilanewas contained in a deuterated solvent; otherwise, an NMR solvent wasused as an internal standard. All the δ values are shown in ppm.Microwave reaction was performed using an Initiator produced by Biotage.

LCMS spectra were measured using an Acquity SQD (quadrupole) produced byWaters Corporation under the following conditions.

Column: Acquity UPLC (trade mark) BEH C18, 2.1×50 mm, 1.7 μm (producedby Waters Corporation)

MS detection: ESI positive

UV detection: 254 and 210 nm

Column flow rate: 0.5 mL/min

Mobile phase: Water/acetonitrile (0.1% formic acid)

Injection volume: 1 μL gradient

Time (min) Water Acetonitrile 0 95 5 0.1 95 5 2.1 5 95 3.0 STOP

Preparative reversed-phase HPLC purification was performed using apreparative separation system available from Gilson, Inc.

Column: CombiPrep Pro C18, 50×30 mml.D., S-5 μm (produced by YMC)

UV detection: 254 nm

Column flow rate: 40 mL/min

Mobile phase: Water/acetonitrile (0.1% formic acid)

Injection volume: 0.1 to 1 mL

The following are the abbreviations used and the meaning of each.

s: singlet

d: doublet

t: triplet

q: quartet

dd: double doublet

dt: double triplet

td: triple doublet

tt: triple triplet

ddd: double double doublet

ddt: double double triplet

dtd: double triple doublet

tdd: triple double doublet

m: multiplet

br: broad

brs: broad singlet

CDI: carbonyldiimidazole

DMSO-d₆: deuterated dimethyl sulfoxide

CDCl₃: deuterated chloroform

CD₃OD: deuterated methanol

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

DMA: N,N-dimethylacetamide

NMP: 1-methyl-2-pyrrolidinone

DMSO: dimethyl sulfoxide

HATU:(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaneiminium hexafluorophosphate

DIAD: diisopropyl azodicarboxylate

DIPEA: diisopropylethylamine

DME: 1,2-dimethoxyethane

Reference Example 1: Synthesis of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acidStep 1: Synthesis of1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A suspension of 3.0 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-aminesynthesized in accordance with the procedure described in InternationalPublication No. WO2007/126841, 3.4 g of iodocyclopentane, and 4.8 g ofpotassium carbonate in 30 mL of DMF was heated to 80° C. and stirred for18 hours. After the resulting mixture was cooled to room temperature,200 mL of water was added thereto, followed by filtration of the formedsolid. The solid was washed with water and dried, thereby obtaining 3.7g of the title compound as a yellow solid.

Physical Properties: m/z[M+H]⁺ 330.1.

Step 2: Synthesis of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

21 g of 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineobtained in step 1, 42 ml of 2-diethylaminoethanol, and 2.24 g ofPd(PPh₃)₂Cl₂ were dissolved in 120 ml of NMP, and the inside of thesystem was replaced with carbon monoxide, followed by heating to 120° C.After stirring for 2 hours, the resulting mixture was cooled to roomtemperature, and 50 ml of methanol was added thereto. 19 ml of a 5Naqueous sodium hydroxide solution was further added thereto and stirredfor 30 minutes. After addition of water, the aqueous layer was washedwith ethyl acetate, and the washed aqueous layer was adjusted withhydrochloric acid to a pH of 3. The precipitated solid was collected byfiltration, washed with water, and dried, thereby obtaining 9.8 g of thetitle compound as a pale yellow solid.

Physical Properties: m/z[M+H]⁺ 248.3.

Reference Example 2: Synthesis of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid Step 1: Synthesis of1-(4,4-dimethylcyclohexyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

6.08 mL of diisopropyl azodicarboxylate was added to a solution of 4 gof 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 5.89 g of4,4-dimethylcyclohexanol, and 8.0 g of triphenylphosphine in 30 mL ofTHF at room temperature, followed by stirring overnight. Afterconcentration, the residue was purified by silica gel chromatography(hexane->hexane/ethyl acetate=1/1), thereby obtaining 3.9 g of the titlecompound as a white solid.

Physical Properties: m/z[M+H]⁺ 373.1.

Step 2: Synthesis of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid

3.14 g of1-(4,4-dimethylcyclohexyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineobtained in step 1, 5.61 mL of 2-diethylaminoethanol, and 297 mg ofPd(PPh₃)₂Cl_(z) were dissolved in 15 mL of NMP, and the inside of thesystem was replaced with carbon monoxide, followed by heating to 120° C.After stirring for 2 hours, the resulting mixture was cooled to roomtemperature, and 15 mL of methanol was added thereto. 6.9 mL of a 5Naqueous sodium hydroxide solution was further added thereto and stirredfor 30 minutes. After addition of water, the aqueous layer was washedwith ethyl acetate, and the washed aqueous layer was adjusted withhydrochloric acid to a pH of 3. The precipitated solid was collected byfiltration, washed with water, and dried, thereby obtaining 2.2 g of thetitle compound as a pale yellow solid.

Physical Properties: m/z[M+H]⁺ 290.3.

Reference Example 3: Synthesis of4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acidStep 1: Synthesis of methyl4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate

3.33 g of triethylamine and 1.35 g of a1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex were added to a suspension of 4.45 gof 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine in 45 mLof methanol. The mixture was stirred in a carbon monoxide atmosphere inan autoclave at 0.5 MPa and at 100° C. for 3 hours. After cooling, themixture was dissolved in chloroform, washed with water, and dried overanhydrous sodium sulfate. The dried mixture was then filtered andconcentrated. The obtained residue was purified by silica gel columnchromatography (hexane-ethyl acetate), and the obtained solid wassuspended and washed with hexane-ethyl acetate. After filtration, thesolid was dried at 70° C. under reduced pressure, thereby obtaining 2.37g of the title compound as a pale orange solid.

Physical Properties: m/z[M+H]⁺ 250.1.

Step 2: Synthesis of 4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

2.23 g of methyl4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylateobtained in step 1 of Reference Example 3 was suspended in 33 mL ofmethanol, and 3.58 mL of a 5M aqueous sodium hydroxide solution wasadded thereto. The mixture was heated under reflux with stirring for 30minutes. After cooling, the reaction solution was neutralized with a 5Mhydrochloric acid aqueous solution and diluted with water to collect theprecipitated solid by filtration. The obtained solid was dried at 60° C.under reduced pressure, thereby obtaining 2.05 g of the title compoundas a colorless solid.

Physical Properties: m/z[M+H]⁺ 236.3.

Reference Example 4: Synthesis of4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid Step 1: Synthesis of1-(4,4-difluorocyclohexyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1.6 mL of diisopropyl azodicarboxylate was added to a solution of 1.6 gof 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 1.0 g of4,4-difluorocyclohexanol, and 2.1 g of triphenylphosphine in 50 mL ofTHF at room temperature, followed by stirring overnight. Afterconcentration, the mixture was suspended and washed with methanol andfiltered. The obtained solid was dried at 60° C. under reduced pressure,thereby obtaining 1.5 g of the title compound as a colorless solid.

Physical Properties: m/z[M+H]⁺ 380.2.

Step 2: Synthesis of methyl4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate

A mixture solution of 1.5 g of1-(4,4-difluorocyclohexyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amineobtained in step 1 of Reference Example 4, 330 mg of a1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, and 3 mL ofN,N-diisopropylethylamine in 30 mL of methanol was stirred in a carbonmonoxide atmosphere in an autoclave at 0.45 MPa and at 100° C. for 2hours. After cooling, the mixture was concentrated and purified bysilica gel column chromatography (hexane-ethyl acetate). Afterconcentration, the obtained crude product was re-purified by basicsilica gel chromatography (hexane-ethyl acetate), and the obtained solidwas suspended and washed with hexane-ethyl acetate, followed byfiltration and drying under reduced pressure, thereby obtaining 650 mgof the title compound as a colorless solid.

Physical Properties: m/z[M+H]⁺ 312.1.

Step 3: Synthesis of4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid

According to the synthesis procedure of step 2 in Reference Example 3,using 653 mg ofmethyl-4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylateobtained in step 2 above, instead of methyl4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate usedin step 2 of Reference Example 3, 605 mg of the title compound wasobtained as a colorless solid.

Physical Properties: m/z[M+H]⁺ 298.1.

Reference Example 5: Synthesis of tert-butyl5-amino-3-methyl-1H-pyrazole-1-carboxylate

75 g of 5-methyl-1H-pyrazol-3-amine was dissolved in 800 mL ofdichloromethane, and 750 mL of a 5N NaOH aqueous solution was addedthereto. 184.5 g of di-tert-butyl dicarbonate was added to the solution,and the mixture was stirred at room temperature for 3 days. Water wasadded to the solution, followed by extraction with chloroform. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate. The organic solution was concentrated under reduced pressure,and the obtained solid was washed with hexane, thereby obtaining 68 g ofthe title compound as a white solid.

Physical Properties: m/z[M+H]⁺ 198.1

NMR (DMSO-d6) δ ppm 1.51 (s, 9H), 1.98 (s, 3H), 5.13 (s, 1H), 6.23 (s,2H).

Reference Example 6: Synthesis of4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid Step1: Synthesis of 4-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

5.79 mL of DIAD was added to a solution of 4.0 g of4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, 2.58 g of propan-2-ol, and7.51 g of triphenylphosphine in 30 mL of tetrahydrofuran. The reactionsolution was stirred for 18 hours. The reaction solution wasconcentrated, and the obtained residue was purified by silica gelchromatography (hexane->hexane/ethyl acetate=1/1), thereby obtaining 4.0g of the title compound as a pale yellow solid.

Physical Properties: m/z[M+H]⁺ 322.0.

Step 2: Synthesis of5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

30 mL of 1,2-dimethoxyethane and 30 mL of 28% ammonia water were addedto 3 g of 4-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidineobtained in step 1 above, and the mixture was stirred in a stainlesspressure-resistant tube at 115° C. for 18 hours. 300 mL of water wasadded to the reaction solution, and the obtained solid was washed withwater, thereby obtaining 2.0 g of the title compound as a white solid.

Physical Properties: m/z[M+H]⁺ 303.1.

Step 3: Synthesis of 4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

3.8 g of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtainedin step 2 above, 8.3 mL of 2-diethylamino ethanol, and 0.44 g ofPd(PPh₃)₂Cl_(z) were dissolved in 10 mL of NMP, and the inside of thesystem was replaced with carbon monoxide, followed by heating to 120° C.After stirring for 2 hours, the reaction mixture was cooled to roomtemperature, and 7 mL of methanol was added thereto. 3.5 mL of a 5Naqueous sodium hydroxide solution was further added, and the mixture wasstirred for 30 minutes. After addition of water, the aqueous layer waswashed with ethyl acetate and adjusted with hydrochloric acid to a pH of3, followed by filtration of the precipitated solid. The obtained solidwas washed with water and dried, thereby obtaining 0.670 g of the titlecompound as a pale yellow solid.

Physical Properties: m/z[M+H]⁺ 221.2.

Reference Example 7: Synthesis of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acidStep 1: Synthesis of 7-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

A mixture solution of 29.3 g of2-(4,6-dichloropyrimidin-5-yl)acetaldehyde, 13.4 g of tert-butylamine,and 29.7 g of N,N-diisopropylethylamine in 200 mL of ethanol was stirredwith heating under reflux for 2 hours. After cooling, the reactionmixture was concentrated. The residue was diluted with ethyl acetate,washed with water and subsequently with a saturated aqueous sodiumchloride solution. The obtained organic layer was dried over anhydroussodium sulfate, filtered, and concentrated. The obtained residue waspurified by silica gel chromatography, thereby obtaining 21.5 g of thetitle compound as a colorless solid.

Physical Properties: m/z[M+H]⁺ 210.0.

Step 2: Synthesis of7-(tert-butyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

46.7 g of N-iodosuccinimide was added to a solution of 36 g of7-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine obtained in step 1in 360 mL of DMF, and the mixture was stirred at room temperature for 3days. The mixture was diluted with ethyl acetate and washed with water 3times, followed by washing with a saturated aqueous sodium chloridesolution. The obtained organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated. The obtained solid was suspendedand washed with hexane-ethyl acetate, and filtered, followed by dryingunder reduced pressure, thereby obtaining 45.5 g of the title compoundas a pale orange solid.

Physical Properties: m/z[M+H]⁺ 335.9.

Step 3: Synthesis of7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A suspension of 52 g of7-(tert-butyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine obtained instep 2 in 180 mL of THF and 180 mL of 28% ammonia water was stirred at120° C. for 14 hours in an autoclave. After cooling, the mixture wasdiluted with water to collect the precipitated solid by filtration,followed by drying at 60° C. under reduced pressure, thereby obtaining52 g of the title compound as a colorless solid.

Physical Properties: m/z[M+H]⁺ 317.3.

Step 4: Synthesis of methyl4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

A suspension of 15 g of7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained instep 3, 1.94 g of a 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, and 13.2 mL of triethylamine in 150mL of methanol was stirred in a carbon monoxide atmosphere in anautoclave at 100° C. and 0.45 MPa for 1.5 hours. After cooling, thereaction solution was concentrated and purified by silica gelchromatography (hexane-ethyl acetate). The obtained solid was suspendedand washed with hexane-ethyl acetate, filtrated, and dried under reducedpressure, thereby obtaining 9.70 g of the title compound as a dark redsolid.

Physical Properties: m/z[M+H]⁺ 249.3.

Step 5: 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid

23.4 mL of a 5M aqueous sodium hydroxide solution was added to asuspension of 9.70 g of methyl4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 4 in 97 mL of methanol. The mixture was stirred withheating under reflux for 2 hours. After cooling, the mixture wasneutralized with a 5M hydrochloric acid aqueous solution to precipitatea brown solid. After dilution with water, the solid was filtered anddried at 60° C. under reduced pressure, thereby obtaining 8.0 g of thetitle compound as a brown solid.

Physical Properties: m/z[M+H]⁺ 235.2.

Reference Example 8: Synthesis of7-(tert-butyl)-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Step1: Synthesis of 1-(4,6-dichloropyrimidin-5-yl)propan-2-ol

1 g of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde was dissolved in 20 mLof THF, and the reactor was cooled to −78° C. 4.36 mL of amethylmagnesium bromide diethyl ether solution (3 mol/L) was slowlyadded dropwise thereto. At the same temperature, the mixture was stirredfor 1 hour, and a saturated aqueous ammonium chloride solution wasslowly added thereto to terminate the reaction. The reaction mixture wasstirred at room temperature for 10 minutes and placed in a separatoryfunnel, followed by extraction with ethyl acetate. The organic layer waswashed with a saturated aqueous sodium chloride solution, and then driedover sodium sulfate to remove the solvent. The residue was purified bybasic silica gel chromatography (hexane/ethyl acetate=1/0->3/1), therebyobtaining 446 mg of the title compound as a colorless oil.

Physical Properties: m/z[M+H]⁺ 207.0.

Step 2: Synthesis of 1-(4,6-dichloropyrimidin-5-yl)propan-2-one

246 mg of 1-(4,6-dichloropyrimidin-5-yl)propan-2-ol obtained in step 1was dissolved in 2.5 mL of dichloromethane, and 1.0 g of a Dess-Martinreagent was added thereto, followed by stirring at room temperature for1 hour. A 10% sodium thiosulfate aqueous solution and saturated sodiumbicarbonate water were added to the reaction solution, and the mixturewas further stirred for 30 minutes. The reaction mixture was extractedwith chloroform, and the organic layer was washed with water and asaturated aqueous sodium chloride solution, followed by addition ofsodium sulfate for drying. After removal of the solvent, the residue waspurified by silica gel chromatography (hexane/ethyl acetate=1/0->3/1),thereby obtaining 198 mg of the title compound as a yellow solid.

Physical Properties: m/z[M+H]⁺ 205.0.

Step 3: Synthesis of1-(4-(tert-butylamino)-6-chloropyrimidin-5-yl)propan-2-one

198 mg of 1-(4,6-dichloropyrimidin-5-yl)propan-2-one obtained in step 2,122 μL of tert-butylamine, and 252 μL of diisopropylethylamine weredissolved in 2 mL of ethanol, and the solution was stirred at 90° C.overnight.

After the reaction mixture was concentrated, the residue was purified bysilica gel chromatography (hexane/ethyl acetate=1/0->3/1), therebyobtaining 64 mg of the title compound as a colorless oil.

Physical Properties: m/z[M+H]⁺ 242.1.

Step 4: Synthesis of7-(tert-butyl)-4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

64 mg of 1-(4-(tert-butylamino)-6-chloropyrimidin-5-yl)propan-2-oneobtained in step 3 and 42 μL of acetic acid were dissolved in 5.5 mL ofethanol, and the solution was reacted in a microwave reactor at 120° C.for 1 hour. After removal of the solvent, the residue was purified bysilica gel chromatography (hexane/ethyl acetate=1/0->4/1), therebyobtaining 54 mg of the title compound as a colorless oil.

Physical Properties: m/z[M+H]⁺ 224.1.

Step 5: Synthesis of7-(tert-butyl)-4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

7-(tert-butyl)-4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine obtained instep 4 was dissolved in 1.5 mL of DMF. 64 mg of N-iodosuccinimide wasadded thereto, and the mixture was stirred at room temperatureovernight. A 10% aqueous sodium thiosulfate solution was added to thereaction solution to terminate the reaction, and the reaction solutionwas extracted with ethyl acetate. The organic layer was washed withwater and a saturated aqueous sodium chloride solution, and dried oversodium sulfate, followed by removal of the solvent. The residue waspurified by silica gel chromatography (hexane/ethyl acetate=1/0->4/1),thereby obtaining 69 mg of the title compound as a white solid.

Physical Properties: m/z[M+H]⁺ 349.9.

Step 6:7-(tert-butyl)-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

60 mg of7-(tert-butyl)-4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidineobtained in step 5 was reacted with 600 μL of DME and 600 μL of ammoniawater in a pressure-resistant tube at 115° C. for 12 hours. After aircooling, water was added to the reaction mixture. The obtained whitesolid was filtered and dried, thereby obtaining 45 mg of the titlecompound.

Physical Properties: m/z[M+H]⁺ 331.0.

Example 1: Synthesis of4-amino-1-cyclopentyl-N-(5-ethyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

30 mg of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid obtained in step 2 of Reference Example 1, 16 mg of5-ethyl-1H-pyrazol-3-amine, and 55 mg of HATU were dissolved in 1 mL ofDMF, and 62 μL of diisopropylethylamine was added thereto. The mixturewas stirred at room temperature for 18 hours, and water was added to thereaction solution, followed by extraction with chloroform. The organiclayer was washed with water, and dried over anhydrous magnesium sulfate,followed by concentration of the organic solution under reducedpressure. The residue was purified by silica gel chromatography(chloroform->chloroform/methanol=10/1), thereby obtaining 29 mg of thetitle compound as a white solid.

Example 2: Synthesis of4-amino-1-cyclopentyl-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using5-(furan-2-yl)-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (55%) was obtained as a brownish solid.

Example 3: Synthesis of4-amino-1-cyclopentyl-N-(5-(furan-3-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using5-(furan-3-yl)-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (76%) was obtained as a brownish solid.

Example 4: Synthesis of4-amino-1-cyclopentyl-N-(5-(thiophen-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using5-(thiophen-2-yl)-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, the title compound (60%) was obtained as abrownish solid.

Example 5: Synthesis of4-amino-1-cyclopentyl-N-(5-phenyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using5-phenyl-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine, thetitle compound (77%) was obtained as a brownish solid.

Example 6: Synthesis of4-amino-1-cyclopentyl-N-(5-cyclopentyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using5-cyclopentyl-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (63%) was obtained as a brownish solid.

Example 7: Synthesis of4-amino-1-cyclopentyl-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using5-cyclopropyl-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (68%) was obtained as a brownish solid.

Example 8: Synthesis of4-amino-1-cyclopentyl-N-(3-propyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using5-propyl-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine, thetitle compound (70%) was obtained as a brownish solid.

Example 9: Synthesis of4-amino-1-cyclopentyl-N-(1,3-dimethyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using1,3-dimethyl-1H-pyrazol-5-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (28%) was obtained as a white solid.

Example 10: Synthesis of4-amino-1-cyclopentyl-N-(5-isopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using5-isopropyl-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (89%) was obtained as a brownish solid.

Example 11: Synthesis of4-amino-1-cyclobutyl-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using bromocyclobutane instead of iodocyclopentane,4-amino-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid wasobtained as a brownish solid. According to the procedure of Example 1,using 4-amino-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, the title compound (50%) was obtained as abrownish solid.

Example 12: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-((1-methylcyclopropyl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using (1-methylcyclopropyl)methyl methanesulfonate instead ofiodocyclopentane,4-amino-7-((1-methylcyclopropyl)methyl)-7H-pyrazolo[3,4-d]pyrimidine-5-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 1, using4-amino-7-((1-methylcyclopropyl)methyl)-7H-pyrazolo[3,4-d]pyrimidine-5-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid andusing 5-methyl-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (38%) was obtained as a brownish solid.

Example 13: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using 2,2,2-trifluoroethyl methanesulfonate instead ofiodocyclopentane,4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 1, using4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, the title compound (51%) was obtained as awhite solid.

Example 14: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using 3-bromo-1,1,1-trifluoropropane instead ofiodocyclopentane,4-amino-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a white solid. According to the procedure ofExample 1, using4-amino-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, the title compound (84%) was obtained as awhite solid.

Example 15: Synthesis of4-amino-1-(sec-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using 2-bromobutane instead of iodocyclopentane,4-amino-7-(sec-butyl)-7H-pyrazolo[2,3-d]pyrimidine-5-carboxylic acid wasobtained as a white solid. According to the procedure of Example 1,using 4-amino-7-(sec-butyl)-7H-pyrazolo[2,3-d]pyrimidine-5-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, the title compound (62%) was obtained as abrownish solid.

Example 16: Synthesis of4-amino-1-(cyclobutylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using (bromomethyl)cyclobutane instead of iodocyclopentane,4-amino-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a white solid. According to the procedure ofExample 1, using4-amino-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, the title compound was obtained as abrownish solid (63%).

Example 17: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using (bromomethyl)cyclobutane instead of iodocyclopentane,4-amino-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a white solid. According to the procedure ofExample 1, using 5-bromo-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, and using4-amino-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,the title compound was obtained as a brownish solid (42%).

Example 18: Synthesis of4-amino-1-(cyclopropylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using (bromomethyl)cyclopropane instead of iodocyclopentane,4-amino-1-(cyclopropylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a white solid. According to the procedure ofExample 1, using4-amino-1-(cyclopropylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, the title compound was obtained as abrownish solid (71%).

Example 19: Synthesis of4-amino-1-(cyclopentylmethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using (bromomethyl)cyclopentane instead of iodocyclopentane,4-amino-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 1, using4-amino-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid, and using5-methyl-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine, thetitle compound (53%) was obtained as a white solid.

Example 20: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using (bromomethyl)cyclopentane instead of iodocyclopentane,4-amino-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 1, using 5-bromo-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, and using4-amino-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,the title compound (61%) was obtained as a brownish solid.

Example 21: Synthesis of4-amino-1-isopropyl-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using 2-bromopropane instead of iodocyclopentane,4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid wasobtained as a white solid. According to the procedure of Example 1,using 5-(trifluoromethyl)-1H-pyrazol-3-amine instead of5-ethyl-1H-pyrazol-3-amine, and using4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acidinstead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,the title compound (22%) was obtained as a brownish solid.

Example 22: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using 2-bromopropane instead of iodocyclopentane,4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid wasobtained as a white solid. According to the procedure of Example 1,using 5-bromo-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine,and using 4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,the title compound (50%) was obtained as a brownish solid.

Example 23: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using [(1S,2R)-2-methylcyclohexyl]methanesulfonate instead ofiodocyclopentane, 4-amino-1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acidwas obtained as a brownish solid. According to the procedure of Example1, using 4-amino-1-((1R,2R)-2-methylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acidinstead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid andusing 5-methyl-1H-pyrazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (35%) was obtained as a white solid.

Example 24: Synthesis of4-amino-1-(4,4-dimethylcyclohexyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

35 mg of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid obtained in step 2 in Reference Example 2, 14 mg of5-methyl-1H-pyrazol-3-amine, and 55 mg of HATU were dissolved in 1 mL ofDMF, and 63 μL of diisopropylethylamine was added thereto. Afterstirring at room temperature for 18 hours, water was added to thereaction solution, followed by extraction with chloroform. The organiclayer was washed with water and dried over anhydrous magnesium sulfate,followed by concentration of the organic solution under reducedpressure. The residue was purified by silica gel chromatography(chloroform->chloroform/methanol=10/1), thereby obtaining 27 mg of thetitle compound as a white solid.

Example 25: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the procedure of Example 24, using5-bromo-1H-pyrazol-3-amine instead of 5-methyl-1H-pyrazol-3-amine, thetitle compound (53%) was obtained as a brownish solid.

Example 26: Synthesis of4-amino-1-(3,3-dimethylcyclobutyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 2, using 3,3-dimethylcyclobutanol instead of4,4-dimethylcyclohexanol,4-amino-1-(3,3-dimethylcyclobutyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a white solid. According to the procedure ofExample 24, using4-amino-1-(3,3-dimethylcyclobutyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid, the title compound (47%) was obtained as a brownish solid.

Example 27: Synthesis of4-amino-1-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 2, using bicyclo[2.2.1]heptan-2-ol instead of4,4-dimethylcyclohexanol,4-amino-1-(bicyclo[2.2.1]heptane)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 24, using4-amino-1-(bicyclo[2.2.1]heptane)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid, the title compound (57%) was obtained as a brownish solid.

Example 28: Synthesis of4-amino-1-(bicyclo[2.2.1]heptan-2-yl)-N-(5-bromo-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 2, using bicyclo[2.2.1]heptan-2-ol instead of4,4-dimethylcyclohexanol,4-amino-1-(bicyclo[2.2.1]heptane)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 24, using4-amino-1-(bicyclo[2.2.1]heptane)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid, and using 3-bromo-1H-pyrazol-5-amine instead of5-methyl-1H-pyrazol-3-amine, the title compound (61%) was obtained as abrownish solid.

Example 29: Synthesis of1-(adamantan-2-yl)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 2, using adamantan-2-ol instead of 4,4-dimethylcyclohexanol,1-(adamantan-2-yl)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 24, using1-(adamantan-2-yl)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid, the title compound (69%) was obtained as a brownish solid.

Example 30: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-1-((2S,3R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 2, using (2S,3S)-2,6,6-trimethylnorpinan-3-ol instead of4,4-dimethylcyclohexanol,4-amino-1-((2S,3R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 24, using4-amino-1-((2S,3R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid, the title compound (61%) was obtained as a brownish solid.

Example 31: Synthesis of4-amino-1-(3-fluoroprop-1-en-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 2, using 1,3-difluoropropan-2-ol instead of4,4-dimethylcyclohexanol,4-amino-1-(3-fluoroprop-1-en-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid was obtained as a brownish solid. According to the procedure ofExample 24, using4-amino-1-(3-fluoroprop-1-en-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid, the title compound (65%) was obtained as a brownish solid.

Example 32: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 2, using cyclohexanol instead of 4,4-dimethylcyclohexanol,4-amino-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid wasobtained as a brownish solid. According to the procedure of Example 24,using 4-amino-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid and using 3-bromo-1H-pyrazol-5-amine instead of5-methyl-1H-pyrazol-3-amine, the title compound (23%) was obtained as abrownish solid.

Example 33: Synthesis of4-amino-1-cyclohexyl-N-(5-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 2, using cyclohexanol instead of 4,4-dimethylcyclohexanol,4-amino-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid wasobtained as a brownish solid. According to the procedure of Example 24,using 4-amino-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid instead of4-amino-1-(4,4-dimethylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid, and using 5-(difluoromethyl)-1H-pyrazol-3-amine instead of5-methyl-1H-pyrazol-3-amine, the title compound (41%) was obtained as abrownish solid.

Example 34: Synthesis of4-amino-1-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

429 mg of HATU was added to a suspension of 177 mg of4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acidobtained in step 2 of Reference Example 3, 109 mg of5-methyl-1H-pyrazol-3-amine, and 0.393 mL of N,N-diisopropylethylaminein 4 mL of DMF, and the mixture was stirred at room temperatureovernight. 100 μL of a 5M aqueous sodium hydroxide solution was added tothe reaction solution, and stirred for 1 hour. Thereafter, the mixturewas neutralized with a 5M hydrochloric acid aqueous solution. Afterextraction with chloroform, the extract was dried over anhydrous sodiumsulfate, filtered, and concentrated. The obtained residue was suspendedand washed with methanol, filtered, and dried at 60° C. under reducedpressure, thereby obtaining 97 mg of the title compound as a colorlesssolid.

Example 35: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the procedure of Example 34, using3-bromo-1H-pyrazol-5-amine instead of 5-methyl-1H-pyrazol-3-amine, thetitle compound was obtained as a pale brownish solid (25%).

Example 36: Synthesis of4-amino-1-(tert-butyl)-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the procedure of Example 34, using5-(trifluoromethyl)-1H-pyrazol-3-amine instead of5-methyl-1H-pyrazol-3-amine, the title compound (72%) was obtained as apale brownish solid.

Example 37: Synthesis of4-amino-1-(tert-butyl)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the procedure of Example 34, using3-(furan-2-yl)-1H-pyrazol-5-amine instead of5-methyl-1H-pyrazol-3-amine, the title compound (32%) was obtained as apale brownish solid.

Example 38: Synthesis of4-amino-1-(tert-butyl)-N-(5-cyano-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the procedure of Example 34, using5-amino-1H-pyrazole-3-carbonitrile instead of5-methyl-1H-pyrazol-3-amine, the title compound (22%) was obtained as abrownish solid.

Example 39: Synthesis of4-amino-1-(tert-butyl)-N-(5-ethyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 34, using3-ethyl-1H-pyrazol-5-amine instead of 5-methyl-1H-pyrazol-3-amine,followed by purification with preparative reversed-phase HPLC, the titlecompound (55%) was obtained as a brownish solid.

Example 40: Synthesis of4-amino-1-(tert-butyl)-N-(5-isopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 34, using3-isopropyl-1H-pyrazol-5-amine instead of 5-methyl-1H-pyrazol-3-amine,followed by purification with preparative reversed-phase HPLC, the titlecompound (81%) was obtained as a brownish solid.

Example 41: Synthesis of4-amino-1-(tert-butyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 34, using3-cyclopropyl-1H-pyrazol-5-amine instead of 5-methyl-1H-pyrazol-3-amine,followed by purification with preparative reversed-phase HPLC, the titlecompound (69%) was obtained as a brownish solid.

Example 42: Synthesis of4-amino-1-(tert-butyl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the procedure of Example 34, using3-cyclobutyl-1H-pyrazol-5-amine instead of 5-methyl-1H-pyrazol-3-amine,followed by purification with preparative reversed-phase HPLC, the titlecompound (33%) was obtained as a brownish solid.

Example 43: Synthesis of4-amino-1-(4,4-difluorocyclohexyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 34, using4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid obtained in step 3 of Reference Example 4 instead of4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid ofExample 34, the title compound (21%) was obtained as a colorless solid.

Example 44: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 34, using4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid obtained in step 3 of Reference Example 4 instead of4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid ofExample 34, and using 3-bromo-1H-pyrazol-5-amine instead of5-methyl-1H-pyrazol-3-amine, the title compound (33%) was obtained as acolorless solid.

Example 45: Synthesis of4-amino-7-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

121 mg of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtainedin step 2 of Reference Example 6, 197 mg of tert-butyl5-amino-3-methyl-1H-pyrazole-1-carboxylate obtained in Reference Example5, and 120 μL of 1,8-diazabicyclo[5.4.0]undec-7-ene were dissolved in 2mL of DMA. 33 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane was further added thereto, and the mixturewas stirred in a carbon monoxide atmosphere at 110° C. for 4 hours. Theresidue obtained by concentrating the reaction mixture was purified bysilica gel chromatography (hexane/ethyl acetate=1/1->ethylacetate/methanol=10/1), thereby obtaining 52 mg of the title compound asa pale brown solid.

Example 46: Synthesis of4-amino-7-(1-fluoropropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 6, using 1-fluoropropan-2-ol instead of propan-2-ol,7-(1-fluoropropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine wasobtained as a white solid. According to the procedure of Example 45,using 7-(1-fluoropropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound was obtained as a brownish solid (90%).

Example 47: Synthesis of4-amino-7-(4,4-dimethylcyclohexyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 6, using 4,4-dimethylcyclohexanol instead of propan-2-ol,7-(4,4-dimethylcyclohexyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine wasobtained as a yellow solid. According to the procedure of Example 45,using7-(4,4-dimethylcyclohexyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (31%) was obtained as a brownish solid.

Example 48: Synthesis of4-amino-7-(tert-butyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

A solution of 6.0 g of7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained instep 3 of Reference Example 7, 7.48 g of tert-butyl5-amino-3-methyl-pyrazole-1-carboxylate obtained in Reference Example 5,5.67 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1.55 g of a1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex in 200 mL of DMA was stirred in acarbon monoxide atmosphere at 100° C. for 3 hours. The reaction solutionwas concentrated and then purified by silica gel chromatography(hexane-ethyl acetate-methanol), followed by purification by basicsilica gel chromatography, thereby obtaining 3.24 g of the titlecompound as a brownish solid.

Example 49: Synthesis of4-amino-7-(tert-butyl)-N-(5-(furan-2-yl)-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 48, using5-(furan-2-yl)-1H-pyrazol-3-amine instead of tert-butyl5-amino-3-methyl-pyrazole-1-carboxylate used in Example 48, the titlecompound (42%) was obtained as a pale brownish solid.

Example 50: Synthesis of4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 1-fluoro-2-methylpropane-2-amine hydrochloride insteadof tert-butylamine,7-(1-fluoro-2-methylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a white solid. According to the procedure of Example 48,using7-(1-fluoro-2-methylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (70%) was obtained as a brownish solid.

Example 51: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 1-methylcyclopropane amine hydrochloride instead oftert-butylamine,5-iodo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine wasobtained as a white solid. According to the procedure of Example 48,using 5-iodo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (37%) was obtained as a brownish solid.

Example 52: Synthesis of4-amino-7-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 2-cyclopropylpropane-2-amine hydrochloride instead oftert-butylamine,7-(2-cyclopropylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a white solid. According to the procedure of Example 48,using7-(2-cyclopropylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (60%) was obtained as a brownish solid.

Example 53: Synthesis of4-amino-7-(1-methoxy-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 2-methoxy-2-methylpropan-2-amine instead oftert-butylamine,5-iodo-7-(1-methoxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a white solid. According to the procedure of Example 48,using5-iodo-7-(1-methoxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (50%) was obtained as a brownish solid.

Example 54: Synthesis of4-amino-7-(1-(fluoromethyl)cyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 1-(fluoromethyl)cyclopropane amine hydrochlorideinstead of tert-butylamine,7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a white solid. According to the procedure of Example 48,using7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (60%) was obtained as a brownish solid.

Example 55: Synthesis of4-amino-7-(1-(difluoromethyl)cyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 1-(difluoromethyl)cyclopropane amine hydrochlorideinstead of tert-butylamine,7-(1-(difluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a yellow solid. According to the procedure of Example48, using7-(1-(difluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (40%) was obtained as a brownish solid.

Example 56: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2-(thiophen-2-yl)propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 2-(thiophen-2-yl)propan-2-amine instead oftert-butylamine,5-iodo-7-(2-(thiophen-2-yl)propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a yellow solid. According to the procedure of Example48, using5-iodo-7-(2-(thiophen-2-yl)propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (70%) was obtained as a brownish solid.

Example 57: Synthesis of4-amino-7-(3,3-difluorocyclopentyl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 3,3-difluorocyclopentane amine hydrochloride instead oftert-butylamine,7-(3,3-difluorocyclopentyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a yellow solid. According to the procedure of Example48, using7-(3,3-difluorocyclopentyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (50%) was obtained as a brownish solid.

Example 58: Synthesis of4-amino-7-(bicyclo[1.1.1]pentan-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using bicyclo[1.1.1]pentane-1-amine hydrochloride instead oftert-butylamine,7-(bicyclo[1.1.1]pentan-1-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidinewas obtained. According to the procedure of Example 48, using7-(bicyclo[1.1.1]pentan-1-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (36%) was obtained as a colorless solid.

Example 59: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 1-methylcyclopentane amine hydrochloride instead oftert-butylamine,5-iodo-7-(1-methylcyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine wasobtained as a white solid. According to the procedure of Example 48,using 5-iodo-7-(1-methylcyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (20%) was obtained as a brownish solid.

Example 60: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2-phenylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 2-phenylpropan-2-amine instead of tert-butylamine,5-iodo-7-(2-phenylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine wasobtained as a yellow solid. According to the procedure of Example 48,using 5-iodo-7-(2-phenylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (41%) was obtained as a brownish solid.

Example 61: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(2,3,3-trimethylbutan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 2,3,3-trimethylbutan-2-amine instead oftert-butylamine,5-iodo-7-(2,3,3-trimethylbutan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a white solid. According to the procedure of Example 48,using5-iodo-7-(2,3,3-trimethylbutan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (60%) was obtained as a brownish solid.

Example 62: Synthesis of4-amino-7-(2,3-dimethylbutan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 2,3-dimethylbutane-2-amine hydrochloride instead oftert-butylamine,7-(2,3-dimethylbutan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine wasobtained as a white solid. According to the procedure of Example 48,using7-(2,3-dimethylbutan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (50%) was obtained as a brownish solid.

Example 63: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

40 mg of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid obtained in step 5 of Reference Example 7 was suspended in 2 mL ofDMF, and 33 mg of 3-bromo-1H-pyrazol-5-amine, 89 μL ofdiisopropylethylamine, and 78 mg of HATU were added thereto, followed bystirring at room temperature overnight. 2 ml, of an aqueous sodiumhydroxide solution (1 mol/L) was added to the reaction mixture, and themixture was stirred at room temperature for 1 hour. Thereafter, thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with water and a saturated aqueous sodiumchloride solution, and dried over sodium sulfate. After concentration,the residue was purified by silica gel chromatography (ethylacetate/methanol=1/0->10/1), thereby obtaining 6.5 mg of the titlecompound as a white solid.

Example 64: Synthesis of4-amino-7-(tert-butyl)-N-(5-(methoxymethyl)-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 63, using5-(methoxymethyl)-1H-pyrazol-3-amine instead of3-bromo-1H-pyrazol-5-amine, the title compound (24%) was obtained as awhite solid.

Example 65: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 63, using4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acidobtained in step 3 of Reference Example 6 instead of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,the title compound (20%) was obtained as a brownish solid.

Example 66: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of step 3 in Reference Example 6, using7-(1-fluoro-2-methylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineused in Example 50 instead of7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine,4-amino-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid was obtained. According to the procedure of Example 63, using4-amino-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid instead of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,the title compound (29%) was obtained as a white solid.

Example 67: Synthesis of4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of step 3 in Reference Example 6, using5-iodo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine usedin Example 51 instead of7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine,4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid was obtained. According to the procedure of Example 63, using4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid instead of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,the title compound (19%) was obtained as a white solid.

Example 68: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1 to 5 in ReferenceExample 7, using 1-methylcyclobutane-amine hydrochloride instead oftert-butylamine, 4-amino-7-(methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid was obtainedas a white solid. According to the procedure of Example 63, using4-amino-7-(methyl cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid instead of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of3-bromo-1H-pyrazol-5-amine, the title compound (15%) was obtained as abrownish solid.

Example 69: Synthesis of4-amino-7-cyclobutyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1 to 5 in ReferenceExample 7, using cyclobutane amine instead of tert-butylamine,4-amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid wasobtained. According to the procedure of Example 63, using4-amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acidinstead of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of3-bromo-1H-pyrazol-5-amine, the title compound (8%) was obtained as abrownish solid.

Example 70: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(tert-pentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1 to 5 in ReferenceExample 7, using 2-methylbutan-2-amine instead of tert-butylamine,4-amino-7-(tert-pentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acidwas obtained as a white solid. According to the procedure of Example 63,using 4-amino-7-(tert-pentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid instead of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of3-bromo-1H-pyrazol-5-amine, the title compound (16%) was obtained as abrownish solid.

Example 71: Synthesis of4-amino-7-(bicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1 to 5 in ReferenceExample 7, using bicyclo[2.2.1]heptan-2-amine instead oftert-butylamine,4-amino-7-(bicyclo[2.2.1]heptan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid was obtained as a white solid. According to the procedure ofExample 63, using4-amino-7-(bicyclo[2.2.1]heptan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid instead of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of3-bromo-1H-pyrazol-5-amine, the title compound (8%) was obtained as abrownish solid.

Example 72: Synthesis of4-amino-7-cyclopentyl-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1 to 3 in ReferenceExample 6, using cyclopentanol instead of propan-2-ol,4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid wasobtained as a white solid. According to the procedure of Example 63,using 4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid instead of4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,and using 5-methyl-1H-pyrazol-3-amine instead of3-bromo-1H-pyrazol-5-amine, the title compound (15%) was obtained as awhite solid.

Example 73: Synthesis of4-amino-7-(tert-butyl)-6-methyl-N-(3-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 48, using7-(tert-butyl)-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineobtained in step 6 of Reference Example 8 instead of7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine to perform areaction, the title compound (6.7%) was obtained as a white solid.

Example 74: Synthesis of7-([1,1′-bi(cyclopropan)]-1-yl)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis procedures of steps 1, 2, and 3 in ReferenceExample 7, using 1-cyclopropyl cyclopropane amine hydrochloride insteadof tert-butylamine,7-([1,1′-bi(cyclopropan)]-1-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-aminewas obtained as a brownish solid. According to the procedure of Example48, using7-([1,1′-bi(cyclopropan)]-1-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineinstead of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, thetitle compound (59%) was obtained as a brownish solid.

Example 75: Synthesis of4-amino-6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamideStep 1: Synthesis of methyl4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

12.1 g of triethylamine and 2.25 g of a[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex were added to a suspension of 18.85 g of5-iodo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amineobtained as an intermediate in Example 51 in 180 mL of methanol. Themixture was stirred in a carbon monoxide atmosphere in an autoclave at0.5 MPa and at 100° C. for 1.5 hours. After cooling, the solvent wasremoved, and the residue was dissolved in 300 mL of chloroform. 20 g ofCelite was added thereto, followed by stirring at room temperature for 1hour. The insoluble matter was removed by filtration, and the filtratewas washed with water and a saturated aqueous sodium chloride solution,dried over anhydrous magnesium sulfate, and filtered, followed byconcentration. The obtained residue was purified by silica gel columnchromatography (chloroform/methanol=100/1->20/1), and the solvent wasremoved. The obtained solid was suspended and washed with ethyl acetate,thereby obtaining 11.6 g of the title compound.

Step 2: Synthesis of methyl4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

1.71 g of methyl4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 1 was dissolved in 17 mL of DMF, and 1.39 g ofN-chlorosuccinimide was added thereto, followed by stirring at 50° C.for 2 hours. 80 mL of a 10% sodium thiosulfate aqueous solution and 120mL of water were added to the reaction solution, and the mixture wasstirred with ice cooling for 3 hours, followed by stirring at roomtemperature overnight. The precipitate was collected by filtration andwashed with water, thereby obtaining 1.13 g of the title compound.

Step 3: Synthesis of4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid

272 mg of methyl4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 2 was dissolved in 2.7 mL of THF and 2.7 mL ofmethanol, and 1.45 mL of a lithium hydroxide aqueous solution (4 mol/L)was added thereto, followed by stirring at room temperature overnight.20 mL of water and a 2N hydrochloric acid aqueous solution were added tothe reaction solution to acidify the solution, thereby obtaining aprecipitate. The organic solvent was removed, and the residue wasstirred with ice cooling for 1 hour, followed by filtration, therebyobtaining 248 mg of the title compound.

Step 4: Synthesis of4-amino-6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

2.5 mL of DMF was added to 48 mg of4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid obtained in step 3, and 33 mg of 1-hydroxybenztriazole and 38 mg of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride werefurther added thereto, followed by stirring at room temperature for 1.5hours. 106 mg of tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylatesynthesized in Reference Example 5 was added to the reaction solution,and the mixture was cooled to 0° C. Thereafter, 0.45 mL of a lithiumhexamethyldisilazide solution (1M THF) was added thereto, followed bystirring at 0° C. for 30 minutes. 5 mL of a 1N aqueous sodium hydroxidesolution was added to the reaction solution, and the mixture was stirredat room temperature for 1 hour. The reaction solution was partitionedbetween ethyl acetate and water. The organic layer was washed with waterthree times and washed with a saturated aqueous sodium chloridesolution, followed by drying over anhydrous sodium sulfate. Afterfiltration, the resulting solution was concentrated. The residue waspurified by silica gel column (ethyl acetate/methanol=1/0->8/1), therebyobtaining 15 mg of the title compound.

Example 76: Synthesis of4-amino-6-bromo-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamideStep 1: Synthesis of methyl4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

2.3 g of methyl4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 1 of Example 75 was dissolved in 47 mL of chloroform,and 3.3 g of N-bromosuccinimide was added thereto, followed by stirringat room temperature for 3 days. The reaction solution was partitionedbetween chloroform and a 10% sodium thiosulfate aqueous solution. Theorganic layer was washed with water and a saturated aqueous sodiumchloride solution, and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. Methanol and water were addedto the residue to form a suspension, and methanol was removed. Theresidue was stirred at 0° C. for 1 hour, and the solid was collected byfiltration, thereby obtaining 2.50 g of the title compound.

Step 2: Synthesis of4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid

According to the procedure of step 3 in Example 75, using 1.10 g ofmethyl4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 1, the title compound (97%) was obtained.

Step 3: Synthesis of4-amino-6-bromo-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of step 4 in Example 75, using 238 mg of4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid obtained in step 2, the title compound (26%) was obtained.

Example 77: Synthesis of4-amino-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamideStep 1: Synthesis of4-amino-6-methoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid

560 mg of methyl4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 2 of Example 75 was suspended in 10 mL of THF, and 121mg of 4-dimethylamino pyridine and 1.52 g of di-tert-butyl dicarbonatewere added to the suspension with stirring. The mixture was stirred at50° C. for 1 hour. After cooling, the reaction solution wasconcentrated, and partitioned between ethyl acetate and water. Theorganic layer was washed with water and a saturated aqueous sodiumchloride solution. Anhydrous sodium sulfate was added, and the mixturewas filtered, and concentrated. 10 mL of methanol was added to theresidue, and 1 mL of sodium methoxide (methanol solution of about 5mol/L) was added thereto with stirring, followed by stirring at 50° C.for 1 hour. After cooling, the mixture was concentrated, and the residuewas partitioned between chloroform and saturated ammonium chloride. Theorganic layer was washed with water and a saturated aqueous sodiumchloride solution. Anhydrous sodium sulfate was added, and the mixturewas filtered and concentrated. 1 ml, of dichloromethane and 2 mL oftrifluoroacetic acid were added to the residue, and the mixture wasstirred at room temperature for 1 hour. After concentration, the residuewas partitioned between chloroform and a saturated aqueous sodiumbicarbonate solution. The organic layer was washed with water and asaturated aqueous sodium chloride solution. Anhydrous sodium sulfate wasadded, and the mixture was filtered and concentrated. The residue wasdissolved in 20 mL of methanol, and 2.3 mL of an aqueous sodiumhydroxide solution (4 mol/L) was added thereto, and the mixture wasstirred at 50° C. for 1 hour, followed by further stirring at 80° C. for1 hour. After cooling, 20 mL of water and a 2N hydrochloric acid aqueoussolution were added to the reaction solution to acidify the solution,thereby obtaining a precipitate. After the organic solvent was removed,the residue was stirred with ice cooling for 1 hour and filtered,thereby obtaining 417 mg of the title compound.

Step 2: Synthesis of4-amino-6-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of step 4 in Example 75, using 30 mg of4-amino-6-methoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid obtained in step 1, the title compound (36%) was obtained.

Example 78: Synthesis of4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of step 4 in Example 75, using 30 mg of4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid that was synthesized using7-(1-fluoro-2-methylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amineobtained as an intermediate in Example 50 in accordance with theprocedures of steps 1 to 3 in Example 75, the title compound (16%) wasobtained.

Example 79: Synthesis of4-amino-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

35 mg of4-amino-6-bromo-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamideobtained in Example 76 was dissolved in 1 mL of DMF. 1.7 mg of copperiodide, 87 μL of 2-methyl-3-butyn-1-ol, 31 μL of triethylamine, and 10mg of tetrakis triphenylphosphine palladium were added thereto anddegassed, followed by stirring at 100° C. for 2 hours. The reactionsolution was partitioned between chloroform and water. The organic layerwas washed with a saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate, and filtered, followed by concentration. Theresidue was purified by silica gel column (ethylacetate/methanol=1/0->4/1), thereby obtaining 14 mg of the titlecompound.

Example 80: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using 3-ethynylpyridineinstead of 2-methyl-3-butyn-1-ol, the title compound (72%) was obtained.

Example 81: Synthesis of4-amino-6-((1-hydroxycyclopentyl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using1-ethynylcyclopentan-1-ol instead of 2-methyl-3-butyn-1-ol, the titlecompound (18%) was obtained.

Example 82: Synthesis of4-amino-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using4-ethynyl-1-methyl-1H-pyrazole instead of 2-methyl-3-butyn-1-ol, thetitle compound (43%) was obtained.

Example 83: Synthesis of4-amino-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using5-ethynyl-1-methyl-1H-imidazole instead of 2-methyl-3-butyn-1-ol, thetitle compound (57%) was obtained.

Example 84: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-(3-morpholino-1-propyn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using4-(2-propyn-1-yl)morpholine instead of 2-methyl-3-butyn-1-ol, the titlecompound (39%) was obtained.

Example 85: Synthesis of4-amino-6-(3-(1-hydroxycyclobutyl)-1-propyne)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using1-(2-propyn-1-yl)cyclobutan-1-ol instead of 2-methyl-3-butyn-1-ol, thetitle compound (58%) was obtained.

Example 86: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using4-ethynyltetrahydro-2H-pyrane instead of 2-methyl-3-butyn-1-ol, thetitle compound (56%) was obtained.

Example 87: Synthesis of4-amino-N-(5-methyl-1H-pyrazol-3-yl)-6-((1-methyl-1H-pyrazol-3-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using3-ethynyl-1-methyl-pyrazole instead of 2-methyl-3-butyn-1-ol, the titlecompound (28%) was obtained.

Example 88: Synthesis of4-amino-6-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of Example 79, using1-ethynylimidazo[1,2-b]pyridazine instead of 2-methyl-3-butyn-1-ol, thetitle compound (19%) was obtained.

Example 89: Synthesis of4-amino-6-ethoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamideStep 1: Synthesis of4-amino-6-ethoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid

630 mg of methyl4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 1 of Example 76 was suspended in 10 mL of THF. 119 mgof 4-dimethylamino pyridine and 1.27 g of di-tert-butyl dicarbonate wereadded thereto with stirring, and the solution was stirred at 50° C. for1 hour. After cooling, the reaction solution was concentrated, andpartitioned between ethyl acetate and water. The organic layer waswashed with water and a saturated aqueous sodium chloride solution.Anhydrous sodium sulfate was added thereto, and the mixture was filteredand concentrated. 15 mL of ethanol was added to the residue, and 2.28 mLof sodium ethoxide (28% ethanol solution) was also added with stirring,followed by stirring at room temperature overnight. The reactionsolution was neutralized with a 2N hydrochloric acid aqueous solution,and then concentrated. The residue was partitioned between chloroformand water. The organic layer was washed with a saturated aqueous sodiumchloride solution, and anhydrous sodium sulfate was added thereto. Afterfiltration, the resulting solution was concentrated. 3 mL ofdichloromethane and 6 mL of trifluoroacetic acid were added to theresidue, and the mixture was stirred at room temperature for 1.5 hours.After concentration, the residue was partitioned between chloroform anda saturated aqueous sodium bicarbonate solution. The organic layer waswashed with water and a saturated aqueous sodium chloride solution, andanhydrous sodium sulfate was added thereto, followed by filtration andconcentration. The residue was dissolved in 20 mL of methanol, and 3.88mL of an aqueous sodium hydroxide solution (4 mol/L) was added thereto,followed by stirring at 60° C. for 3 hours. After cooling, 50 mL ofwater and a 2N hydrochloric acid aqueous solution were added to thereaction solution to acidify the solution, thereby obtaining aprecipitate. The organic solvent was removed, and the residue wasstirred with ice cooling for 1 hour, followed by filtration, therebyobtaining 432 mg of the title compound.

Step 2: Synthesis of4-amino-6-ethoxy-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

1.2 mL of DMF was added to 67 mg of4-amino-6-ethoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid obtained in step 1, and 41 mg of 1-hydroxybenzotriazole and 51 mgof 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride werefurther added thereto, followed by stirring at room temperature for 2hours. 143 mg of tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylatesynthesized in Reference Example 5 was added to the reaction solution,and 0.60 mL of a sodium tert-butoxide solution (2M THF) was addedthereto at room temperature. After stirring for 30 minutes, 5 mL of a 1Naqueous sodium hydroxide solution was added to the reaction solution,followed by stirring at room temperature for 1 hour. The reactionsolution was partitioned between ethyl acetate and water, and theorganic layer was washed with water three times, and washed with asaturated aqueous sodium chloride solution. After drying over anhydroussodium sulfate, the resulting solution was filtered and concentrated.The residue was purified by silica gel column (ethylacetate/methanol=1/0->5/1), thereby obtaining 33 mg of the titlecompound.

Example 90: Synthesis of(R)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamideStep 1: Synthesis of methyl4-(bis(tert-butoxycarbonyl)amino)-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

351 mg of methyl4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 2 of Example 75 was suspended in 6.3 mL of THF, and 76mg of 4-dimethylamino pyridine and 818 mg of di-tert-butyl dicarbonatewere added thereto with stirring. The solution was then stirred at 60°C. for 1 hour. After cooling, the reaction solution was concentrated,and the residue was purified by silica gel column (hexane/ethylacetate=4/1->2/3), thereby obtaining 523 mg of the title compound.

Step 2: Synthesis of (R)-methyl4-(bis(tert-butoxycarbonyl)amino)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

86 μL of (R)-(−)-tetrahydrofurfuryl alcohol was added to a suspension of35 mg of sodium hydride (60%) in 1 mL of DMF with ice cooling, and themixture was stirred at room temperature for 30 minutes. A solution of212 mg of methyl4-(bis(tert-butoxycarbonyl)amino)-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 1 in 1 mL of DMF was added to this solution, and themixture was stirred at room temperature for 1.5 hours. The reactionsolution was partitioned between chloroform and water, and the organiclayer was washed with a saturated aqueous sodium chloride solution.Anhydrous sodium sulfate was added thereto, and the mixture wasfiltered, and then concentrated. The residue was purified by silica gelcolumn (hexane/ethyl acetate=4/1->2/3), thereby obtaining 141 mg of thetitle compound.

Step 3: Synthesis of(R)-4-amino-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid

1.5 mL of chloroform and 2 mL of trifluoroacetic acid were added to 141mg of (R)-methyl4-(bis(tert-butoxycarbonyl)amino)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateobtained in step 2, and the mixture was stirred at room temperature for1.5 hours. After concentration, 2 mL of methanol and 2 mL oftetrahydrofuran were added to the residue, and 1.29 mL of an aqueoussodium hydroxide solution (4 mol/L) was further added thereto, followedby stirring at 60° C. for 3 hours. After cooling, 10 mL of water, and a2N hydrochloric acid aqueous solution were added to the reactionsolution to acidify the solution, thereby obtaining a precipitate. Afterthe organic solvent was removed, the residue was stirred with icecooling for 1 hour, followed by filtration, thereby obtaining 52 mg ofthe title compound.

Step 4: Synthesis of(R)-4-amino-N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the procedure of step 2 in Example 89, using 52 mg of(R)-4-amino-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid obtained in step 1, the title compound (39%) was obtained.

Comparative Example 1: Synthesis of4-amino-1-cyclopentyl-N-(4-fluoro-1H-indazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedure of Example 1, using4-fluoro-1H-indazol-3-amine instead of 5-ethyl-1H-pyrazol-3-amine, thetitle compound (48%) was obtained as a brownish solid.

Comparative Example 2: Synthesis of4-amino-1-cyclobutyl-N-(4-methylthiazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using bromocyclobutane instead of iodocyclopentane,4-amino-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid wasobtained as a brownish solid. According to the synthesis procedure ofExample 1, using4-amino-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acidinstead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,and using 4-methylthiazol-2-amine instead of 5-ethyl-1H-pyrazol-3-amine,the title compound (83%) was obtained as a brownish solid.

Comparative Example 3: Synthesis of4-amino-1-cyclobutyl-N-(4-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis procedures of steps 1 and 2 in ReferenceExample 1, using bromocyclobutane instead of iodocyclopentane,4-amino-1-cyclobutyl-1H-pyrazolo[2,3-d]pyrimidine-3-carboxylic acid wasobtained as a brownish solid. According to the synthesis procedure ofExample 1, using4-amino-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acidinstead of4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid,and using 4-methyl-1H-imidazol-2-amine instead of5-ethyl-1H-pyrazol-3-amine, the title compound (58%) was obtained as abrownish solid.

Comparative Example 4: Synthesis of1-(tert-butyl)-3-(p-tolyl)pyrazolo[3,4-d]pyrimidin-4-amine

In accordance with the synthesis procedure described in TetrahedronLetters, 52(44), 5761-5763; 2011, the title compound (30%) was obtainedas a white solid.

Tables 1 to 14 show the formulae and physical properties of thecompounds obtained in the Examples and Comparative Examples.

TABLE 1 Comp. of Ex. Formula Physical Properties 1

m/z [M + H]+ 342.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J = 7.6 Hz,3H), 1.67- 1.70 (m, 2H), 1.92-1.95 (m, 2H), 2.08-2.12 (m, 4H), 2.60 (q,J = 7.6 Hz, 2H), 5.22-5.25 (m, 1H), 6.42 (s, 1H), 8.23 (brs, 1H), 8.24(s, 1H), 8.31 (brs, 1H), 10.37 (s, 1H), 12.31 (s, 1H). 2

m/z [M + H]+ 379.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.71 (m, 2H),1.90-2.00 (m, 2H), 2.09-2.12 (m, 4H), 5.21-5.28 (m, 1 H), 6.63 (s, 1 H),6.88 (m, 1H), 6.91 (brs, 1H), 7.79 (s, 1H), 8.11 (brs, 1H), 8.25 (s,1H), 8.48 (brs, 1H), 10.70 (s, 1H), 13.16 (s, 1H). 3

m/z [M + H]+ 379.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.71 (m, 2H),1.93-1.97 (m, 2H), 2.09-2.14 (m, 4H), 5.23-5.26 (m, 1H), 6.91-6.93 (m,2H), 7.77 (s, 1H), 8.11 (brs, 1H), 8.17 (s, 1H), 8.25 (s, 1H), 8.52(brs, 1H), 10.61 (s, 1H), 12.90 (s, 1H). 4

m/z [M + H]+ 395.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69 (m, 2H),1.90-2.00 (m, 2H), 2.11-2.13 (m, 4H), 5.21-5.29 (m, 1H), 6.85-6.87 (m,1H), 7.14 (m, 1H), 7.50 (brs, 1H), 7.60 (brs, 1H), 8.12 (brs, 1H), 8.25(s, 1H), 8.47 (brs, 1H), 10.69 (s, 1H), 13.15 (s, 1H). 5

m/z [M + H]+ 389.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.71 (m, 2H),1.94-1.99 (m, 2H), 2.10-2.13 (m, 4H), 5.23-5.27 (m, 1H), 7.07 (s, 1H),7.34-7.38 (m, 1H), 7.44-7.48 (m, 2H), 7.78-7.80 (m, 2H), 8.12 (brs, 1H),8.25 (s, 1H), 8.52 (brs, 1H), 10.63 (s, 1H), 13.12 (s, 1H). 6

m/z [M + H]+ 381.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.72 (m, 8H),1.91-2.03 (m, 4H), 2.07-2.12 (m, 4H), 3.00-3.04 (m, 1H), 5.21-5.25 (m,1H), 6.41 (s, 1H), 8.08 (brs, 1H), 8.23 (s, 1H), 8.50 (brs, 1H), 10.38(s, 1H), 12.32 (s, 1H). 7

m/z [M + H]+ 353.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.69-0.72 (m, 2H),0.91-0.93 (m, 2H), 1.65-1.70 (m, 2H), 1.88-1.96 (m, 3H), 2.07-2.12 (m,4H), 5.21-5.23 (m, 1H), 6.29 (s, 1H), 8.08 (brs, 1H), 8.23 (s, 1H), 8.48(brs, 1H), 10.36 (s, 1H), 12.33 (s, 1H).Note: In the tables and figures, “Comp.” denotes compounds, and “Ex.”denotes Examples.

TABLE 2  8

m/z [M + H] + 355.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J = 7.2 Hz,3H), 1.57-1.64 (m, 2H), 1.66-1.88 (m, 2H), 1.91-1.98 (m, 2H), 2.07- 2.12(m, 4H), 2.56 (t, J = 7.6 Hz, 2H), 5.21-5.25 (m, 1H), 6.41 (s, 1H), 8.08(brs, 1H), 8.24 (s, 1H), 8.50 (brs, 1H), 10.38 (s, 1H), 12.31 (s, 1H). 9

m/z [M + H] + 341.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.71 (m, 2H),1.89-1.98 (m, 2H), 2.06-2.09 (m, 4H), 2.13 (s, 3H), 3.60 (s, 3H), 5.04-5.26 (m, 1H), 6.03 (s, 1H), 8.09 (brs, 1H), 8.24 (s, 1H), 8.36 (brs,1H), 10.49 (s, 1H). 10

m/z [M + H] + 355.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J = 6.8 Hz,6H), 1.65- 1.70 (m, 2H), 1.90-1.97 (m, 2H), 2.08-2.12 (m, 4H), 2.92-2.95 (m, 1H), 5.21-5.25 (m, 1H), 6.42 (s, 1H), 8.08 (brs, 1H), 8.24 (s,1H), 8.50 (brs, 1H), 10.37 (s, 1H), 12.31 (s, 1H). 11

m/z [M + H] + 313.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.84-1.92 (m, 2H),2.24 (s, 3H), 2.40-2.41 (m, 2H), 2.74-2.84 (m, 2H), 5.30-5.36 (m, 1H),6.40 (s, 1H), 8.10 (brs, 1H), 8.23 (s, 1H), 8.49 (brs, 1H), 10.51 (brs,1H), 12.29 (brs, 1H). 12

m/z [M + H] + 327.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.32-0.35 (m, 2H),0.76-0.78 (m, 2H), 1.22 (s, 3H), 2.23 (s, 3H), 4.25 (s, 2H), 6.40 (s,1H), 8.13 (brs, 1H), 8.26 (s, 1H), 8.52 (brs, 1H), 10.24 (s, 1H), 12.28(s, 1H). 13

m/z [M + H] + 341.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3H),5.29-5.36 (m, 2H), 6.38 (s, 1H), 8.33 (brs, 2H), 8.52 (brs, 1H), 10.32(s, 1H), 12.29 (s, 1H). 14

m/z [M + H] + 355.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3H),3.05-3.16 (m, 2H), 4.61 (t, J = 6.8 Hz, 2H) 6.40 (s, 1H), 8.18 (brs,1H), 8.28 (s, 1H), 8.47 (brs, 1H), 10.52 (s, 1H), 12.28 (s, 1H).

TABLE 3 15

m/z [M + H] + 315.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.68 (t, J = 7.4 Hz,3H), 1.50 (d, J = 6.4 Hz, 3H), 1.81-2.06 (m, 2H), 2.23 (s, 3H),4.81-4.86 (m, 1H), 6.40 (s, 1H), 8.09 (brs, 1H), 8.23 (s, 1H), 8.49(brs, 1H), 10.30 (s, 1H), 12.28 (s, 1H). 16

m/z [M + H] + 327.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.87 (m, 4H),1.92-1.98 (m, 2H), 2.23 (s, 3H), 2.88-2.95 (m, 1H), 4.40 (d, J = 7.2 Hz,2H), 6.37 (s, 1H), 8.12 (brs, 1H), 8.25 (s, 1H), 8.49 (brs, 1H), 10.24(s, 1H), 12.26 (s, 1H). 17

m/z [M + H] + 392.9 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.87 (m, 4H),1.92-1.98 (m, 2H), 2.89-2.93 (m, 1H), 4.43 (d, J = 6.8 Hz, 2H), 6.36 (s,1H), 8.22 (brs, 1H), 8.28 (s, 1H), 8.38 (brs, 1H), 11.45 (s, 1H), 12.81(s, 1H). 18

m/z [M + H] + 313.7 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.43-0.52 (m, 4H),1.34-1.39 (m, 1H), 2.23 (s, 3H), 4.24 (d, J = 6.8 Hz, 2H), 6.38 (s, 1H),8.13 (brs, 1H), 8.25 (s, 1H), 8.50 (brs, 1H), 10.28 (s, 1H), 12.26 (s,1H). 19

m/z [M + H] + 341.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.60 (m, 8H),2.22 (s, 3H), 2.53-2.59 (m, 1H), 4.27-4.30 (m, 2H), 6.37 (s, 1H), 8.12(brs, 1H), 8.25 (s, 1H), 8.50 (brs, 1H), 10.27 (s, 1H), 12.25 (s, 1H).20

m/z [M + H] + 407.7 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.61 (m, 8H),2.53-2.58 (m, 1H), 4.31-4.33 (m, 2H), 6.36 (s, 1H), 8.21 (brs, 1H), 8.27(s, 1H), 8.39 (brs, 1H), 11.46 (s, 1H), 12.81 (s, 1H). 21

m/z [M + H] + 356.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J = 6.8 Hz,6H), 5.09- 5.13 (m, 1H), 6.67 (s, 1H), 8.20 (brs, 1H), 8.27 (s, 1H),8.36 (brs, 1H), 11.39 (s, 1H), 13.40 (s, 1H).

TABLE 4 22

m/z [M + H] + 366.9 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J = 6.8 Hz,6H), 5.07- 5.12 (m, 1H), 6.38 (d, J = 1.6 Hz, 1H), 8.18 (brs, 1H), 8.26(s, 1H), 8.37 (brs, 1H), 11.26 (s, 1H), 12.85 (s, 1H). 23

m/z [M + H] + 355.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.52 (d, J = 6.4 Hz,3H), 1.15- 1.47 (m, 4H), 1.70-1.73 (m, 1H), 1.82-1.84 (m, 3H), 1.20-2.08(m, 1H), 2.23 (s, 3H), 4.31-4.37 (m, 1H), 6.39 (s, 1H), 8.11 (brs, 1H),8.23 (s, 1H), 8.50 (brs, 1H), 10.34 (s, 1H), 12.27 (s, 1H). 24

m/z [M + H] + 369.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.97 (s, 3H), 1.06(s, 3H), 1.39-1.52 (m, 4H), 1.72-1.75 (m, 2H), 2.18-2.27 (m, 2H), 2.23(s, 3H), 4.58-4.64 (m, 1H), 6.40 (s, 1H), 8.08 (brs, 1H), 8.23 (s, 1H),8.52 (brs, 1H), 10.46 (s, 1H), 12.28 (s, 1H). 25

m/z [M + H] + 435.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.97 (s, 3H), 1.05(s, 3H), 1.40-1.53 (m, 4H), 1.76-1.79 (m, 2H), 2.19-2.28 (m, 2H), 4.62-4.63 (m, 1H), 6.38 (s, 1H), 8.18 (brs, 1H), 8.25 (s, 1H), 8.36 (brs,1H), 11.21 (s, 1H), 12.89 (s, 1H). 26

m/z [M + H] + 341.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6H),2.21-2.26 (m, 2H), 2.24 (s, 3H), 2.57-2.62 (m, 2H), 5.32-5.36 (m, 1H),6.41 (s, 1H), 8.09 (brs, 1H), 8.22 (s, 1H), 8.51 (brs, 1H), 10.56 (s,1H), 12.29 (s, 1H). 27

m/z [M + H] + 353.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.69 (m, 7H),2.01 (m, 1H), 2.24 (s, 3H), 2.35 (m, 1H), 2.67 (brs, 1H), 5.08-5.10 (m,1H), 6.40 (s, 1H), 8.08 (brs, 1H), 8.24 (s, 1H), 8.56 (brs, 1H), 10.47(s, 1H), 12.29 (s, 1H). 28

m/z [M + H] + 417.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.67 (m, 7H),2.06 (m, 1H), 2.37 (m, 1H), 2.72 (brs, 1H), 5.80-5.12 (m, 1H), 6.40 (s,1H), 8.18 (brs, 1H), 8.26 (s, 1H), 8.36 (brs, 1H), 11.01 (s, 1H), 12.95(s, 1H).

TABLE 5 29

m/z [M + H] + 393.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.57-1.60 (m, 2H),1.77 (brs, 2H), 1.91-1.98 (m, 6H), 2.24 (s, 3H), 2.33-2.36 (m, 2H), 2.60(brs, 2H), 4.87 (s, 1H), 6.41 (s, 1H), 8.09 (brs, 1H), 8.22 (s, 1H),8.54 (brs, 1H), 10.23 (s, 1H), 12.29 (s, 1H). 30

m/z [M + H] + 395.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.449 (d, J = 7.6Hz, 3H), 1.24 (s, 3H), 1.30 (s, 3H), 1.54 (d, J = 7.6 Hz, 1H), 1.94-1.98(m, 1H), 2.04-2.06 (m, 1H), 2.24 (s, 3H), 2.27-2.35 (m, 2H), 2.82- 2.84(m, 1H), 3.10-3.14 (m, 1H), 5.62-5.75 (m, 1H), 6.41 (s, 1H), 8.25 (brs,1H), 8.26 (s, 1H), 8.50 (brs, 1H), 10.29 (s, 1H), 11.83 (s, 1H). 31

m/z [M + H] + 317.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.24 (s, 3H), 5.59(brs, 1H), 5.61 (s, 1H), 5.72 (s, 1H), 6.42 (brs, 1H), 6.45 (brs, 1H),8.29 (m, 1H), 8.34 (s, 1H), 8.68 (brs, 1H), 10.81 (s, 1H), 12.31 (s,1H). 32

m/z [M + H] + 407.0 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.23-2.10 (m, 10H),4.69-4.71 (m, 1H), 6.38 (s, 1H), 8.19 (brs, 1H), 8.26 (s, 1H), 8.36(brs, 1H), 11.25 (s, 1H), 12.84 (s, 1H). 33

m/z [M + H] + 377.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.72 (m, 1H),1.42-1.51 (m, 2H), 1.70-1.73 (m, 1H), 1.86-2.07 (m, 6H), 4.69-4.72 (m.1H), 6.52 (s, 1H), 7.05-7.08 (m, 1H), 8.12 (brs, 1H), 8.24 (s, 1H), 8.40(brs, 1H), 11.28 (s, 1H), 13.02 (s, 1H). 34

m/z [M + H] + 315.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76 (s, 9H), 2.24(s, 3H), 6.40 (s, 1H), 8.02 (brs, 1H), 8.23 (s, 1H), 8.57 (brs, 1H),10.25 (s, 1H), 12.26 (s, 1H). 35

m/z [M + H] + 380.9 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.77 (s, 9H), 6.39(s, 1H), 8.15 (brs, 1H), 8.25 (m, 1H), 8.35 (brs, 1H), 11.00 (brs, 1H),12.89 (brs, 1H).

TABLE 6 36

m/z [M + H] + 369.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.79 (s, 9H), 6.68(brs, 1H), 8.12 (brs, 1H), 8.26 (s, 1H), 8.36 (brs, 1H), 11.13 (s, 1H),13.44 (s, 1H). 37

m/z [M + H] + 367.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78 (s, 9H),6.61-6.64 (m, 1H), 6.87-6.88 (m, 1H), 6.89-6.92 (m, 1H) 7.79 (s, 1H),8.06 (brs, 1H), 8.24 (s, 1H), 8.55 (brs, 1H), 10.60 (s, 1H), 13.15 (s,1H). 38

mz [M + H] + 326.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.75 (s, 9H), 6.91(brs, 1H), 8.15 (brs, 1H), 8.29 (s, 1H), 8.36 (brs, H), 11.19 (brs, 1H),13.85 (brs, 1H). 39

m/z [M + H] + 329.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J = 7.8 Hz,3H), 1.74 (s, 9H), 2.59 (q, J = 7.8 Hz, 2H), 6.39 (s, 1H), 7.98 (brs,1H), 8.23 (s, 1H), 8.64 (brs, 1H), 10.30 (brs, 1H), 12.27 (brs, 1H). 40

m./z [M + H] + 343.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J = 7.0Hz, 6H), 1.75 (s, 9H), 2.84-2.97 (m, 1H), 6.39 (s, 1H), 8.06 (brs, 1H),8.23 (s, 1H), 8.62 (brs, 1H), 10.29 (brs, 1H), 12.31 (brs, 1H). 41

m/z [M + H] + 341.2 1H NMR (400 MHz, DMSO d6) δ ppm 0.67-0.72 (m, 2H),0.89-0.98 (m, 2H), 1.76 (s, 9H), 1.84-1.91 (m, 1H), 6.26 (s, 1H), 8.05(brs, 1H), 8.22 (s, 1H), 8.59 (brs, 1H), 10.28 (brs, 1H), 12.34 (brs,1H). 42

m/z [M + H] + 355.1 1H NMR (400 MHz, DMSO d6) δ ppm 1.74 (s, 9H),1.77-1.98 (m, 2H), 2.08-2.17 (m, 2H), 2.21-2.32 (m, 2H), 3.44-3.52 (m,1H), 6.45 (s, 1H), 8.06 (br s, 1H), 8.22 (s, 1H), 8.61 (br s, 1H), 10.30(br s, 1H), 12.31 (br s, 1H).

TABLE 7 43

m/z [M + H] + 377.0 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.97-2.34 (m, 11H),4.91-5.00 (m, 1H), 6.37 (s, 1H), 8.09 (brs, 1H), 8.23 (s, 1H), 8.49(brs, 1H), 10.50 (brs, 1H), 12.25 (brs, 1H). 44

m/z [M + H] + 442.9 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.01-2.30 (m, 8H),4.96-4.99 (m, 1H), 6.36 (s, 1H), 8.07-8.22 (br m, 1 H), 8.24-8.26 (m,1H), 8.34-8.37 (br m, 1H), 11.24 (s, 1H), 12.84 (s, 1H). 45

m/z [M + H] + 300.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J = 6.4 Hz,6H), 2.21 (s, 3H), 4.89-4.92 (m, 1H), 6.36 (s, 1H), 8.09 (s, 1H), 8.52(s, 1H), 10.52 (s, 1H). 46

m/z [M + H] + 318.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.49 (d, J = 6.8 Hz,3H), 2.21 (s, 3H), 4.62-4.77 (m, 2H), 5.06-5.15 (m, 1H), 6.37 (s, 1H),8.10 (brs, 1H), 8.52 (s, 1H), 10.57 (s, 1H), 12.11 (s, 1H). 47

m/z [M + H] + 368.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.96 (s, 3H), 1.04(s, 3H), 1.39-1.53 (m, 4H), 1.76-1.90 (m, 4H), 2.21 (s, 3H), 4.48-4.49(m, 1H), 6.38 (s, 1H), 8.09 (s, 1H), 8.60 (s, 1H), 10.45 (s, 1H), 12.12(s, 1H). 48

m/z [M + H] + 314.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70 (s, 9H), 2.19(s, 3H), 6.35 (d, J = 1.5 Hz, 1H), 8.07 (s, 1H), 8.47 (s, 1H), 10.59 (s,1H), 12.07 (s, 1H). 49

m/z [M + H] + 366.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72 (s, 9H), 6.61(s, 1H), 6.85-6.89 (m, 2H), 7.76 (s, 1H), 8.11 (s, 1H), 8.53 (s, 1H),10.85 (s, 1H), 12.99 (s, 1H).

TABLE 8 50

m/z [M + H] + 332.2 1H-NMR 400 MHz, DMSO-d6) δ ppm 1.71 (s, 6H), 2.21(s, 3H), 4.93 (s, 1H), 5.05 (s, 1H), 6.37 (s, 1H), 8.09 (s, 1H), 849 (s,1H), 10.64 (s, 1H), 12.10 (s, 1H). 51

m/z [M + H] + 312.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.97 (m, 2H), 1.13(m, 2H), 1.54 (s, 3H), 2.21 (s, 3H), 6.36 (s, 1H), 8.11 (s, 1H), 8.37(s, 1H), 10.50 (s, 1H), 12.09 (s, 1H). 52

m/z [M + H] + 340.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.56 (m, 4H),1.62 (s, 6H), 1.81 (m, 1H), 2.23 (s, 3H), 6.39 (s, 1H), 8.09 (s, 1H),8.56 (s, 1H), 10.65 (s, 1H), 12.10 (s, 1H). 53

m/z [M + H] + 344.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67 (s, 6H), 2.67(s, 3H), 3.12 (s, 3H), 3.91 (s, 2H), 6.36 (s, 1H), 8.07 (s, 1H), 8.42(s, 1H), 10.63 (s, 1H), 12.10 (s, 1H). 54

m/z [M + H] + 330.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.28 (brs, 4H), 2.21(s, 3H), 4.57 (s, 1H), 4.69 (s, 1H), 6.34 (s, 1H), 8.12 (s, 1H), 8.40(s, 1H), 10.58 (s, 1H), 12.11 (s, 1H). 55

m/z [M + H] + 348.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.45 (m, 4H),2.03 (s, 3H), 5.14 (s, 1H), 6.36 (s, 1H), 8.12 (s, 1H), 8.41 (s, 1H),10.63 (s, 1H), 12.13 (s, 1H). 56

m/z [M + H] + 382.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s, 6H), 2.22(s, 3H), 6.38 (s, 1H), 6.90-6.91 (s, 2H), 7.32-7.33 (m, 1H), 7.96 (s,1H), 8.59 (s, 1H), 10.70 (s, 1H), 12.12 (s, 1H).

TABLE 9 57

m/z [M + H] + 362.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.84-1.92 (m, 2H),2.13-2.68 (m, 4H), 2.22 (s, 3H), 5.25-5.29 (m, 1H), 6.38 (s, 1H), 8.11(s, 1H), 8.52 (s, 1H), 10.58 (s, 1H), 12.13 (s, 1H). 58

m/z [M + H] + 324.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H), 2.38(brs, 6H), 2.68 (brs, 1H), 6.37 (brs, 1H), 8.09 (s, 1H), 8.40 (brs, 1H),10.58 (brs, 1H), 12.10 (brs, 1H). 59

m/z [M + H] + 340.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60 (s, 3H),1.69-1.74 (m, 4H), 2.06-2.09 (m, 2H), 2.21 (s, 3H), 2.43-2.47 (m, 2H),6.36 (s, 1H), 8.08 (s, 1H), 8.48 (s, 1H), 10.61 (s, 1H), 12.10 (s, 1H).60

m/z [M + H] + 376.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 6H), 2.22(s, 3H), 6.40 (s, 1H), 6.99-7.01 (m, 2H), 7.14-7.26 (m, 3H), 7.85 (s,1H), 8.72 (s, 1H), 10.73 (s, 1H), 12.13 (s, 1H). 61

m/z [M + H] + 356.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.89 (s, 9H), 1.82(s, 6H), 2.21 (s, 3H), 6.37 (s, 1H), 8.04 (s, 1H), 8.52 (s, 1H), 10.63(s, 1H), 12.12 (s, 1H). 62

m/z [M + H] + 342.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.68 (d, J = 6.8 Hz,6H), 1.64 (s, 6H), 2.21 (s, 3H), 3.12-3.15 (m, 1H), 6.37 (s, 1H), 8.05(s, 1H), 8.43 (s, 1H), 10.61 (s, 1H), 12.10 (s, 1H) 63

m/z [M + H] + 380.0 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (s, 9 H), 6.13(s, 1 H), 8.14 (s, 1 H), 8.32 (s, 1H) 10.85-10.90 (m, 1 H), 12.98 (s,1H).

TABLE 10 64

m/z [M + H] + 344.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.73 (s, 9 H) 3.27(s, 3 H) 4.40 (s, 2 H) 6.58-6.61 (m, 1 H) 8.10 (s, 1 H) 8.51 (s, 1H),10.73 (s, 1H), 12.49-12.52 (m, 1H). 65

m/z [M + H] + 366.0 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.47 (m, 6H),4.92-4.95 (m, 1H), 6.13 (s, 1H), 7.94 (brs, 1H), 8.11 (s, 1H), 8.13 (s,1H), 8.31 (s, 1H), 10.87 (s, 1H), 12.95 (s, 1H). 66

m/z [M + H] + 398.0 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (brs, 6H) 4.96(brs, 1 H) 5.08 (brs, 1H) 6.14 (s, 1 H) 8.07-8.15 (m, 1 H), 8.31 (s,1H), 10.91 (s, 1H), 12.99 (s, 1H). 67

m/z [M + H] + 378.0 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.06 (m, 2 H),1.12- 1.20 (m, 2 H), 1.55 (s, 3 H), 6.11-6.16 (m, 1 H), 8.11-8.18 (m, 1H), 8.22-8.26 (m, 1 H), 10.74-10.95 (m, 1 H), 12.93 (brs, 1 H). 68

m/z [M + H] + 326.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65 (s, 3H),1.86-1.89 (m, 1H), 1.98-2.03 (m, 1H), 2.31 (s, 3H), 2.31-2.36 (m, 2H),2.62- 2.67 (m, 2H), 6.37 (s, 1H), 8.06 (s, 1H), 8.38 (s, 1H), 10.58 (s,1H), 12.10 (s, 1H). 69

m/z [M + H] + 312.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.90 (m, 2H),2.22 (s, 3H), 2.37-2.47 (m, 4H), 5.10-5.18 (m, 1H), 6.37 (s, 1H), 8.09(s, 1H), 8.67 (s, 1H), 10.57 (s, 1H), 12.12 (s, 1H), 70

m/z [M + H] + 328.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.53 (t, J = 7.4 Hz,3H), 1.68 (s, 6H), 2.17-2.21 (m, 2H), 2.21 (s, 3H), 6.36 (s, 1H), 8.07(s, 1H), 8.43 (s, 1H), 10.62 (s, 1H), 12.10 (s, 1H),

TABLE 11 71

m/z [M + H] + 352.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.26-2.00 (m, 8H),2.21 (s, 3H), 2.32 (m, 1H), 2.42 (m, 1H), 4.62 (m, 1H), 6.37 (s, 1H),8.10 (s, 1H), 8.54 (s, 1H), 10.62 (s, 1H), 12.12 (s, 1H). 72

m/z [M + H] + 326.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.72 (m, 2H),1.79-1.90 (m, 4H), 2.12-2.17 (m, 2H), 2.21 (s, 3H), 5.06-5.09 (m, 1H),6.37 (s, 1H), 8.09 (s, 1H), 8.46 (s, 1H), 10.58(s, 1H), 12.11 (s, 1H).73

m/z [M + H] + 328.1 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.85 (s, 9 H), 2.22(s, 3 H), 2.67 (s, 3 H), 6.40 (s, 1 H), 6.85 (s, 2 H), 8.08 (s, 1 H)10.49 (s, 1 H), 12.11 (s, 1 H). 74

m/z [M + H] + 338.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.28-0.32 (m, 2H),0.35-0.38 (m, 2H), 0.91-0.94 (m, 2H), 1.05-1.08 (m.2H), 1.51-1.53 (m,1H), 2.21 (s, 3H), 6.36 (s, 1H), 8.11 (s, 1H), 8.34 (s, 1H), 10.55 (s,1H), 12.10 (brs, 1H). 75

m/z [M + H] + 346.0 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.24 (m, 4H)1.46 (s, 3H) 2.21 (s, 3H) 6.37 (s, 1H) 7.27 (s, 2H) 8.16 (s, 1H) 10.32(s, 1H) 12.16 (s, 1H). 76

m/z [M + H] + 392.0 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.32 (m, 4H)1.46 (s, 3H) 2.21 (s, 3H) 6.38 (s, 1H) 7.18 (brs, 2H) 8.14 (s, 1H) 10.34(s, 1H) 12.15 (brs, 1H). 77

m/z [M + H] + 342.2 1H-NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09-1.15 (m, 2H) 1.29- 1.34 (m, 2 H) 1.70 (s, 3 H) 2.34 (s, 3 H) 4.26 (s, 3 H) 6.49-6.51 (m, 1 H) 8.34-8.36 (m.1 H) 9.16-9.19 (m, 1 H).

TABLE 12 78

m/z [M + H] + 366.1 1H-NMR (400 MHz, CHLOROFORM-d) δ ppm 1.97-2.02 (m, 6H) 2.35 (s, 3 H) 5.15 (s, 1 H) 5.27 (s, 1 H) 6.57 (s, 1 H) 8.24 (s, 1 H)8.98 (brs, 1 H). 79

m/z [M + H] + 394.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.11 (m, 2 H)1.21- 1.26 (m, 2 H) 1.49 (s, 3 H) 1.60 (s, 6 H) 2.21 (s, 3 H) 5.79 (brs, 1 H) 6.39 (br s, 1 H) 8.19 (s, 1 H) 9.89 (br s, 1 H) 12.24 (br s, 1H). 80

m/z [M + ] + 413.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.25 (m, 2 H)1.25- 1.38 (m, 2 H) 1.55 (s, 3 H) 2.23 (s, 3 H) 6.44 (br s, 1 H) 7.52(dd, J = 7.70, 4.77 Hz, 1 H) 8.14 (br dt, J = 7.97, 1.88 Hz, 1 H) 8.20(s, 1 H) 8.66 (dd, J = 4.77, 1.47 Hz, 1 H) 8.96 (d, J = 1.10 Hz, 1 H)10.32 (brs, 1 H) 12.34 (brs, 1 H). 81

m/z [M + H] + 420.4 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.16 (m, 2 H)1.19- 1.38 (m, 2 H) 1.50 (s, 3 H) 1.69-1.85 (m, 4 H) 1.92-2.07 (m, 2H)2.07-2.17 (m, 2H) 2.22 (s, 3 H) 5.67 (s, 1 H) 6.41 (s, 1 H) 8.32 (s, 1H) 9.91 (s, 1 H) 12.15-12.36 (m, 1 H). 82

m/z [M + H] + 416.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.14 (m, 2 H)1.25- 1.30 (m, 2 H) 1.50 (s, 3 H) 2.22 (s, 3 H) 3.89 (s, 3 H) 6.42 (s, 1H) 7.94 (s, 1 H) 8.17 (s, 1 H) 8.30 (s, 1 H) 10.07 (s, 1 H) 12.22 (s, 1H). 83

m/z [M + H] + 416.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.17 (m, 2 H)1.26- 1.33 (m, 2 H) 1.54 (s, 3 H) 2.21 (s, 3 H) 3.75 (s, 3 H) 6.42 (s, 1H) 7.60 (s, 1 H) 7.86 (s, 1 H) 8.19 (s, 1 H) 10.15 (s, 1 H) 12.21 (s, 1H). 84

m/z [M + H] + 435.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.12 (m, 2 H)1.22- 1.28 (m, 2 H) 1.49 (s, 3 H) 2.21 (s, 3 H) 2.54-2.63 (m, 4 H)3.54-3.61 (m, 4 H) 3.76 (s, 2 H) 6.38 (br s, 1 H) 8.17 (s, 1 H) 10.01(br s, 1 H) 12.17 (br s, 1 H).

TABLE 13 85

m/z [M + H] + 420.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.09 (m, 2 H)1.20- 1.26 (m, 2 H) 1.48 (s, 3 H) 1.50-1.72 (m, 2 H) 1.99-2.10 (m, 2 H)2.10-2.19 (m, 2 H) 2.22 (s, 3 H) 2.93 (s, 2 H) 5.57 (s, 1 H) 6.39 (br s,1 H) 8.15 (s, 1 H) 10.01 (s, 1 H) 12.23 (br s, 1 H). 86

m/z [M + H] + 420.2 1H-NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11 (s, 2 H)1.36 (s, 2 H) 1.59 (s, 3 H) 1.93-2.03 (m, 2 H) 2.05-2.13 (m, 2 H) 2.34(s, 3 H) 3.18 (dt, J = 8.89, 4.54 Hz, 1 H) 3.61 (ddd, J = 11.73, 8.80,2.93 Hz, 2 H) 4.01 (dt, J = 12.10, 4.22 Hz, 2 H) 6.53 (br s, 1 H) 8.35(s, 1 H) 9.79 (s, 1 H). 87

m/z [M + H] + 416.2 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.08 (m, 2H), 1.29(m, 2H), 1.52 (s, 3H), 2.22 (s, 3H), 3.91 (s, 3H), 6.42 (s, 1H), 6.81(m, 1H), 7.86 (m, 1H), 8.14 (m, 1H), 10.13 (s, 1H). 88

m/z [M + H] + 453.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.19 (m, 2H),1.34-1.37 (m, 2H), 1.57 (s, 3H), 2.23 (s, 3H).6.42 (s, 1H), 7.40-1.43(m, 1H), 8.21 (s, 1H), 8.28-8.30 (m, 2H), 8.39 (m, 1H), 8.65- 8.66 (m,1H). 89

m/z [M + H] + 356.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.07 (m, 2 H)1.14- 1.21 (m, 2 H) 1.51 (t, J = 6.96 Hz, 3 H) 1.56 (s, 3 H) 2.20 (s, 3H) 4.43 (q, J = 6.96 Hz, 2 H) 6.36 (s, 1 H) 8.12 (s, 1 H) 9.52 (s, 1 H)12.09 (brs, 1 H). 90

m/z [M + H] + 412.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.07 (m, 2H)1.13- 1.20 (m, 2H) 1.59 (s, 3H) 1.72-1.94 (m, 3H) 1.99-2.09 (m, 1H)2.18-2.22 (m, 3H) 3.64-3.71 (m, 1 H) 3.84-3.95 (m, 1 H) 4.24-4.35 (m,2H) 4.44 (br d, J = 7.33 Hz, 1H) 6.32 (brs, 1H) 8.11 (s, 1H) 9.68 (brs,1H) 12.06 (s, 1H).

TABLE 14 Compound 1 of Comparative Ex.

m/z [M + H] + 381.2 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.85 (m, 2H),1.86-1.90 (m, 2H), 1.99-2.14 (m, 4H), 5.23-5.27 (m, 1H), 6.34 (brs, 2H),7.18-7.22 (m, 1H), 7.58-7.65 (m, 2H).8.12-8.14 (m, 1H), 8.26 (s, (s,1H). Compound 2 of Comparative Ex.

m/z [M + H] + 331.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.85-1.93 (n, 2H),2.32 (s, 3H), 2.39-2.44 (m, 2H), 2.76-2.86 (m, 2H), 5.31-5.40 (m, 1H),6.91 (s, 1H), 8.21 (brs, 2H), 8.30 (s, 1H), 12.64 (brs, 1H). Compound 3of Comparative Ex.

m/z [M + H] + 313.3 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.90 (m, 2H),2.12 (s, 3H), 2.32-2.41 (m, 2H), 2.64-2.76 (n, 2H), 5.27-5.35 (m.1H),6.60 (s, 1H), 7.89 (brs, 1H), 8.20 (s, 1H), 9.46 (brs, 1H). 11.99 (brs,1H). Compound 4 of Comparative Ex.

m/z [M + H] + 282.3 1H-NMR (400 MHz, CHLOROFORM-d) δ ppm 1.84 (s, 9H),2.43 (s, 3H), 5.35 (brs, 2H), 7.33 (d, J = 7.8 Hz.2H), 7.58 (d, J = 7.8Hz, 2H), 8.36 (s, 1H).

Test Example 1: Measurement of RET Inhibitory Activity (In Vitro)

Regarding the conditions for measurement of in vitro inhibitory activityof compounds against RET kinase activity, the website of AnaSpec statesthat Srctide (GEEPLYWSFPAKKK) corresponds to the substrate peptide forreaction to measure RET kinase activity. Thus, the amino acid sequencewas partly modified and biotinylated to prepare biotinylated peptides(biotin-EEPLYWSFPAKKK). The purified recombinant human RET protein usedin the test was purchased from Carna Biosciences, Inc.

To measure the inhibitory activity, first, the compounds of the presentinvention were individually diluted with dimethyl sulfoxide (DMSO)stepwise. Subsequently, RET protein, the substrate peptide (finalconcentration: 250 nM), magnesium chloride (final concentration: 10 mM),ATP (the final concentration: 10 μM), and a solution of the compound ofthe present invention in DMSO (final concentration of DMSO: 2.5%) wereadded to a buffer for kinase reaction (13.5 mM Tris, pH of 7.5, 2 mMdithiothreitol, 0.009% Tween-20). Each of the mixtures was incubated at25° C. for 100 minutes to perform kinase reaction. EDTA was then addedthereto to give a final concentration of 24 mM so that the reaction wasterminated. A detection solution containing Eu-labeledantiphosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA(PerkinElmer) was added thereto, and each mixture was allowed to standat room temperature for 2 hours or more. Finally, the intensity offluorescence under the excitation light with a wavelength of 337 nm wasmeasured with a PHERAstar FS (BMG Labtech) at the two wavelengths of 620nm and 665 nm. The phosphorylation level was calculated from the ratioof the fluorescence intensity at the two wavelengths, and the compoundconcentration at which phosphorylation was inhibited by 50% was definedas the IC50 value (nM).

Table 15 shows IC50 (nM) of the RET (WT) inhibitory activity of thecompounds of the Examples and compounds 1 to 3 of the ComparativeExamples.

Vandetanib is known to have a high inhibitory activity against RET andexhibit a high antitumor effect (e.g., Carlomagno F. Cancer Res. 2002Dec. 15; 62(24): 7284-90). The compounds of the present invention werefound to exhibit in vitro RET inhibitory activity at an equivalent orhigher level than Vandetanib.

Compounds 1 to 3 of Comparative Examples, which do not have a pyrazolylgroup continuous with an amide group, respectively had an IC50 (nM) of451, 752, and 486, exhibiting weak inhibitory activity. In contrast, thecompounds of the present invention had an IC50 (nM) about 40 times, ormore than 40 times, the IC50 (nM) of compounds 1 to 3 of ComparativeExamples, revealing that the compounds of the present invention have ahigh RET inhibitory activity.

TABLE 15 Compound of Examples RET IC50(nM) 1 1.94 2 6.66 4 6.94 5 7.79 78.5 8 3.3 10 10.2 11 1.73 12 8.24 13 6.52 15 4.6 16 4.96 17 4 18 3.2 205.83 21 2.03 22 1.07 24 2.2 25 2.27 26 1 27 0.43 28 0.4 29 0.61 31 1.9732 1.86 33 1.86 34 0.29 35 0.15 36 1 37 5.13 38 1.48 39 1.53 41 10 444.58 45 0.788 46 0.48 47 0.59 48 0.21 49 10.33 50 0.2 51 0.17 52 0.16 530.76 54 0.23 55 0.36 56 0.279 57 1.47 58 0.27 59 0.51 60 3.51 61 0.83 622.27 63 0.15 65 0.23 66 0.15 67 0.15 68 0.337 69 0.46 70 0.79 71 0.4 720.266 73 0.32 74 0.61 75 <0.15 76 0.14 77 1.35 78 <0.15 79 0.07 80 0.0981 0.04 82 0.15 83 0.17 84 0.1 85 0.1 86 0.15 Compound 1 of 451Comparative Examples Compound 2 of 752 Comparative Examples Compound 3of 486 Comparative Examples

Test Example 2: RET Inhibitory Selectivity (In Vitro) Over Other KinaseInhibitory Activity

1) RET Inhibitory Activity Measurement

RET inhibitory activity was measured in the same manner as in TestExample 1.

2) SRC Inhibitory Activity Measurement

Regarding the conditions for measurement of in vitro inhibitory activityof compounds against SRC kinase activity, the price list ofLabChip-series consumable reagents of PerkinElmer shows that FL-Peptide4 corresponds to the substrate peptide for reaction to measure SRCkinase activity. Thus, FL-Peptide 4 was used as a substrate. Thepurified recombinant human SRC protein used in the test was purchasedfrom Carna Biosciences, Inc.

To measure the inhibitory activity, first, the compounds of the presentinvention were individually diluted with dimethyl sulfoxide (DMSO)stepwise. Subsequently, SRC protein, FL-Peptide 4 (final concentration:1.5 μM), magnesium chloride (final concentration: 10 mM), ATP (finalconcentration: 15 μM), and a solution of the compound of the presentinvention in DMSO (final concentration of DMSO: 5%) were added to areaction buffer (100 mM HEPES, pH of 7.0, 1 mM dithiothreitol, 0.003%Brij35, 0.04% Tween-20) containing a phosphatase inhibitor cocktail(PhosSTOP, Roche) and a protease inhibitor cocktail (complete Mini,EDTA-free, Roche) at recommended concentrations. Each mixture wasincubated at 30° C. for 90 minutes to perform kinase reaction. EDTAdiluted with a separation buffer available from PerkinElmer (finalconcentration: 30 mM) was then added thereto to terminate the kinasereaction. Finally, non-phosphorylated substrate peptides (S) andphosphorylated peptides (P) were separated and detected by microchannelcapillary electrophoresis using LabChip EZ Reader II (PerkinElmer). Thephosphorylation level was calculated from the height of the peaks of Sand P, and the compound concentration at which phosphorylation wasinhibited by 50% was defined as IC50 value (nM).

3) LCK Inhibitory Activity Measurement

Regarding the conditions for measurement of in vitro inhibitory activityof compounds against LCK kinase activity, the website of AnaSpec statesthat Srctide (GEEPLYWSFPAKKK) corresponds to the substrate peptide forreaction to measure LCK kinase activity. Thus, the amino acid sequencewas partly modified and biotinylated to prepare biotinylated peptides(biotin-EEPLYWSFPAKKK). The purified recombinant human LCK protein usedin the test was purchased from Carna Biosciences, Inc.

To measure the inhibitory activity, first, the compounds of the presentinvention were individually diluted with dimethyl sulfoxide (DMSO)stepwise. Subsequently, LCK protein, the substrate peptides (finalconcentration: 250 nM), magnesium chloride (final concentration: 10 mM),ATP (final concentration: 50 μM), and a solution of the compound of thepresent invention in DMSO (final concentration of DMSO: 5%) were addedto a buffer for kinase reaction (13.5 mM Tris, pH of 7.5, 2 mMdithiothreitol, 0.009% Tween-20). Each mixture was incubated at 25° C.for 60 minutes to perform kinase reaction. EDTA was then added theretoto give a final concentration of 40 mM so that the reaction wasterminated. A detection solution containing Eu-labeledantiphosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA(PerkinElmer) was added thereto, and each mixture was allowed to standat room temperature for 2 hours or more. Finally, the intensity offluorescence under the excitation light with a wavelength of 337 nm wasmeasured with a PHERAstar FS (BMG Labtech) at the two wavelengths of 620nm and 665 nm. The phosphorylation level was calculated from the ratioof the fluorescence intensity at the two wavelengths, and the compoundconcentration at which phosphorylation was inhibited by 50% was definedas IC50 value (nM).

4) RET Inhibitory Selectivity

From the values obtained in sections 1) and 3) above, SRC inhibitoryactivity IC50 (nM)/RET inhibitory activity IC50 (nM) and LCK inhibitoryactivity IC50 (nM)/RET inhibitory activity IC50 (nM) were calculated,and the RET inhibitory selectivity of the tested compounds was examined.

TABLE 16 SRC IC50(nM)/ LCK IC50(nM)/ Compound of Examples RET IC50(nM)RET IC50(nM) 16 1387.7 282.5 20 1715.3 173.8 27 3737.2 932.6 31 1787.3269.5 34 4296.6 1096.6 36 3210.0 346.0 38 1748.6 526.4 39 652.3 193.5 452659.9 413.7 47 1340.7 220.3 48 2890.5 633.3 50 4060.0 1280.0 51 7188.21882.4 52 3575.0 1131.3 53 1947.4 828.9 56 5896.1 2039.4 57 1381.0 341.558 1818.5 400.0 63 4446.7 906.7 65 6191.3 1160.9 67 3493.3 700.0 682151.3 400.6 71 3030.0 467.5 72 2725.6 469.9 74 3357.4 950.8 79 2171.41785.7 80 4677.8 1244.4 81 3275.0 2275.0 82 5306.7 1200.0 83 2329.4852.9 84 4070.0 3730.0 85 1460.0 743.0 86 2846.7 1273.3 Compound 4 of15.3 15.1 Comparative Examples

As shown in Table 16, compound 4 of Comparative Examples exhibited about15-fold higher inhibitory selectivity for RET over SRC or LCK.

In comparison, the compounds of the present invention exhibitedseveral-hundred-fold to several-thousand-fold higher inhibitoryselectivity for RET over SRC or LCK, revealing its excellent inhibitoryselectivity for RET. The results also suggest that the compounds of thepresent invention have a low likelihood of involving side effects causedby inhibiting kinases other than RET.

Test Example 3: Evaluation of Cell Growth Inhibitory Effect on TumorCell Carrying RET Gene Defect (1)

An in vitro cell-killing test was performed on TT cells (a human thyroidcancer line carrying RET activating mutation (C634W)).

A suspension of TT cells in a 10% FBS-containing Ham's F12K (Kaighn's)medium (produced by Life Technologies Japan) was inoculated into eachwell of a 96-well flat-bottomed microplate in an amount of 5×10³ (0.15mL) for each well, and cultured in an incubator containing 5% carbondioxide at 37° C. overnight (day 0). The compounds of the presentinvention were individually dissolved in dimethyl sulfoxide to give aconcentration of 10 mM, and further diluted with a 10% FBS-containingRPMI1640 medium (produced by Wako Pure Chemical Industries, Ltd.) sothat the compounds of the present invention respectively had a finalconcentration of 40, 12, 4, 1.2, 0.4, 0.12, 0.04, and 0.012 μM. Thecompounds of different concentrations were individually added to wellsof the TT cell-containing culture plate described above in an amount of0.05 mL for each well (day 1), and cultured in an incubator containing5% carbon dioxide at 37° C. for 7 days. After culture (day 8), 0.1 mL ofthe medium was removed from each well, and 0.1 mL of a CellTiter Glo 2.0reagent (Promega Corporation), which is an intracellular ATPluminescence detection reagent, was added thereto, followed by shakingfor 1 minute. After shaking, each culture was allowed to stand at roomtemperature for 15 minutes, and the chemiluminescence was measured witha luminometer to use it as an index of the number of viable cells. Thegrowth rate from day 1 of the compounds with different concentrationswas calculated from the following equations, depending on the value ofT_(day 8) and C_(day 1), to determine the concentration (GI₅₀ (μM)) ofthe tested compounds capable of suppressing cell growth by 50%.T _(day 8) ≥C _(day 1)Growth Rate (%)=(T _(day 8) −C _(day 1))/(C _(day 8) −C_(day 1))×100  1)T: The absorbance of the well to which a tested compound was added.C: The absorbance of the well to which a tested compound was not added.Day 1: The day on which a tested compound was added.Day 8: The day on which evaluation was performed.T _(day 8) <C _(day 1)Growth Rate (%)=(T _(day 8) −C _(day 1))/(C _(day 1))×100  2)T: The absorbance of the well to which a tested compound was added.C: The absorbance of the well to which a tested compound was not added.Day 1: The day on which a tested compound was added.Day 8: The day on which evaluation was performed.

Table 17 shows the results. The compounds of the present inventionexhibited a higher growth inhibitory effect on TT cells than compound 4of Comparative Examples or Vandetanib.

TABLE 17 Compound of Examples TT Cell GI50 (nM) 22 73 26 72 27 53 28 2529 79 34 49 35 23 45 76 46 47 48 21 50 21 51 31 52 10 53 65 54 32 55 2656 45 58 24 59 37 63 14 65 32 66 20 67 8 68 27 69 48 70 82 71 57 72 3073 64 74 59 75 27 76 27 78 76 79 6 80 7 81 <3 82 23 83 14 84 16 85 6 8624 Compound 4 of 8774 Comparative Examples Vandetanib 1143

Test Example 4: Evaluation of Cell Growth Inhibitory Effect on TumorCell Carrying RET Gene Defect (2)

An in vitro cell-killing test was performed on LC-2/ad cells (human lungadenocarcinoma line carrying CCDC6-RET fusion gene).

A suspension of LC-2/ad cells in a 10% FBS-containing RPMI1640 mediumwas inoculated into each well of a 96-well flat-bottomed microplate inan amount of 5×10³ for each well (0.15 mL), and cultured in an incubatorcontaining 5% carbon dioxide at 37° C. overnight (day 0). The compoundsof the present invention were individually dissolved in dimethylsulfoxide to give a concentration of 10 mM, and further diluted with a10% FBS-containing RPMI1640 medium such that the compounds of thepresent invention respectively had a final concentration of 40, 12, 4,1.2, 0.4, 0.12, 0.04, and 0.012 μM. The compounds of differentconcentrations were individually added to each well of the LC-2/adcell-containing culture plate described above in an amount of 0.05 mLfor each well (day 1), and cultured in an incubator containing 5% carbondioxide at 37° C. for 7 days. After culture (day 8), 0.1 mL of themedium was removed from each well, and 0.1 mL of a CellTiter Glo 2.0reagent (Promega Corporation), which is an intracellular ATPluminescence detection reagent, was added thereto, followed by shakingfor 5 minutes. After shaking, each culture was allowed to stand at roomtemperature for 15 minutes, and the chemiluminescence was measured witha luminometer to use it as an index of the number of viable cells. Thegrowth rate from day 1 of the compounds with different concentrationswas calculated from the following equations, depending on the value ofT_(day 8) and C_(day 1), to determine the concentration (GI₅₀ (μM)) ofthe tested compounds capable of suppressing cell growth by 50%.T _(day 8) −C _(day 1)Growth Rate (%)=(T _(day 8) −C _(day 1))/(C _(day 8) −C_(day 1))×100  1)T: The absorbance of the well to which a tested compound was added.C: The absorbance of the well to which a tested compound was not added.Day 1: The day on which a tested compound was added.Day 8: The day on which evaluation was performed.T _(day 8) <C _(day 1)Growth Rate (%)=(T _(day 8) −C _(day 1))/(C _(day 1))×100  2)T: The absorbance of the well to which a tested compound was added.C: The absorbance of the well to which a tested compound was not added.Day 1: The day on which a tested compound was added.Day 8: The day on which evaluation was performed.

Table 18 shows the results. The compounds of the present inventionexhibited a higher growth inhibitory effect on LC-2/ad cells thancompound 4 of Comparative Examples or Vandetanib.

TABLE 18 Compound of Examples LC-2/ad Cell GI50 (nM) 27 246 34 364 35340 46 353 47 285 48 179 50 176 51 153 52 242 53 341 54 128 55 238 56185 58 171 59 203 62 358 63 254 66 209 67 332 68 210 70 229 71 328 72252 73 148 74 337 75 121 76 141 77 218 79 300 81 325 82 185 84 130 85 9986 131 Compound 4 of >10000 Comparative Examples Vandetanib 1709

Test Example 5: Evaluation of Antitumor Effect on In Vivo Model HavingTT (Human Thyroid Cancer Cell Line Carrying RET Activating Mutation)Cells Subcutaneously Implanted

Human thyroid cancer cell lines (TT) were subcutaneously implanted intothe right chest of 6- to 7-week-old BALB/cA Jcl-nu/nu male mice. About 3weeks after the cell implantation, the length (mm) and the width (mm) oftumors found in mouse bodies were measured. After their tumor volume(tumor volume: TV) was calculated, the mice were divided into groups(n=5 or 6) so that the groups had a substantially equal mean TV. The dayon which the mice were divided into groups was determined to be the“grouping day” (day 0 or 1).

Test solutions containing the compounds of the present invention wereprepared at a dose of 100 mg/kg/day, and orally administered to the micefor consecutive 14 days (the first administration day is day 1). Acontrol group was administered a solvent (0.5% HPMC/0.1N HCl).

To determine the index of the antitumor effect, TV of eachdrug-administrated group was measured on day 15, and the tumor volume onday 15 relative to the tumor volume on the grouping day (day 0 or 1)(relative tumor volume: RTV) and T/C (%) were calculated from thefollowing equations to evaluate the antitumor effect. When a groupadministered any of the compounds of the present invention(test-solution-administered group) exhibited a statisticallysignificantly smaller mean RTV (Dunnett's test or Student's t-test,p<0.05) than the mean RTV of the control group, an antitumor effect wasdetermined to be present. FIGS. 1 and 2 and Tables 19 and 20 show theresults. In the figures, the symbol “*” indicates a statisticallysignificant difference.TV (mm³)=(length×width²)/2RTV=(TV on day 15)/(TV on day 0 or day 1)T/C(%)=(the mean RTV of a test-solution-administered group)/(the meanRTV of the control group)×100

To determine the index of the toxicity, the body weight (body weight:BW) of the mice was measured over time, and the mean body weight change(body weight change: BWC (%)) from the grouping day (day 0 or day 1) today 15 was calculated from the following equation (n: the day on whichthe body weight was measured at 2 times/week, and the final measurementday is day 15 on which the final evaluation was performed). FIGS. 3 and4 show the results.BWC (%)=[(BW on day n)−(BW on day 0 or day 1)]/(BW on day 0 or day1)×100

As is clear from FIGS. 1 and 2 and Tables 19 and 20, the compounds ofthe present invention exhibited a remarkable antitumor effect on humanthyroid cancer lines TT carrying RET-activating mutation that weresubcutaneously implanted into nude mice. As shown in FIGS. 3 and 4,toxicity, such as weight loss, was not observed.

TABLE 19 Com- Number TV (mm³) RTV pound of Day 0 Day 15 Day 15 T/C NameAnimals Mean ± SE Mean ± SE Mean ± SE (%) Control 5 139.61 ± 8.75 491.55± 36.88 3.53 ± 0.18 100 Exam- 5 139.31 ± 9.14 205.51 ± 8.30  1.49 ± 0.0942 ple 34 Exam- 5 138.44 ± 9.11 215.87 ± 25.61 1.55 ± 0.13 44 ple 48Exam- 5 143.56 ± 9.24 253.41 ± 28.93 1.76 ± 0.16 50 ple 50 Exam- 5134.36 ± 7.83 190.88 ± 15.75 1.42 ± 0.07 40 ple 51

TABLE 20 Com- Number TV (mm³) RTV pound of Day 1 Day 15 Day 15 T/C NameAnimals Mean ± SE Mean ± SE Mean ± SE (%) Control 6 137.55 ± 14.64381.97 ± 40.17 2.78 ± 0.16 100 Exam- 6 140.33 ± 15.45 131.10 ± 31.120.89 ± 0.11 32 ple 52

Test Example 6: Evaluation of Stability in Hepatic Microsome

Solutions of the tested compounds in DMSO/acetonitrile (the finalconcentration of each tested compound was 1 μM, the final concentrationof DMSO was 0.01%, and the final concentration of acetonitrile was 1%)were individually added to a hepatic microsome mixture solution (mousehepatic microsome with a final concentration of 0.25 mg/mL, a potassiumphosphate buffer with a final concentration of 100 mM, and magnesiumchloride with a final concentration of 3 mM), and each mixture waspre-incubated at 37° C. for 5 minutes. A NADPH-generating system(glucose-6-phosphate with a final concentration of 10 mM, oxidizednicotinamide adenine dinucleotide phosphate with a final concentrationof 1 mM, and glucose-6-phosphate dehydrogenase with a finalconcentration of 1 unit/mL) was added to a portion of each mixturesolution, and metabolic reaction was started. After incubation at 37° C.for 30 minutes, a double amount of ethanol was added thereto toterminate the reaction, thereby obtaining post-reaction samples. Adouble amount of ethanol was added to each of the remaining mixturesolutions, and a NADPH-generating system was further added thereto,thereby obtaining pre-reaction samples. The pre-reaction samples andpost-reaction samples were centrifuged at 2000×g, and their supernatantwas filtered through a glass filter. Each filtrate was then introducedinto LC-MS/MS, and MS/MS peaks of the tested compounds were detected.From the ratio of the post-reaction MS/MS peak to the pre-reaction MS/MSpeak of the tested compounds, the percentage of the remaining testedcompounds (remaining %) was calculated.

The results show that whereas compound 4 of Comparative Examples had aremaining percentage of 0% in any case, the compounds of the presentinvention or salts thereof described in the Examples had a highremaining percentage. This indicates that the compounds of the presentinvention or salts thereof are significantly more stable in mousehepatic microsome than the compound of Comparative Examples.

Test Example 7: Evaluation of Oral Absorption

The compounds of the present invention were suspended or dissolved in0.5% HPMC and 0.1N hydrochloric acid, and orally administered to BALB/cAmice. At a time point of 0.5, 1, 2, 4, and 6 hours after the oraladministration, the blood of the mice was collected from their ocularfundus or facial vein, and centrifuged to obtain plasma. Theconcentration of the compounds in the obtained plasma was measured byLC-MS/MS, and oral absorption was evaluated.

The results reveal that the plasma concentration of the compounds of thepresent invention was sufficient, indicating excellent oral absorption.

The invention claimed is:
 1. A method for treating a malignant tumor,comprising administering an effective amount of a compound representedby Formula (I) below or a salt thereof to a mammal in need thereof:

wherein A is pyrazolyl substituted with n-number of R¹; R¹ is halogen,cyano, substituted or unsubstituted C1-C6 alkyl, substituted orunsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C6-C14aromatic hydrocarbon, or a substituted or unsubstituted C3-C10monocyclic or polycyclic saturated or unsaturated heterocyclic groupcontaining 1 to 3 identical or different heteroatoms selected fromnitrogen, oxygen, and sulfur; R² is substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted orunsubstituted C2-C6 alkenyl, substituted or unsubstituted C3-C7cycloalkenyl, substituted or unsubstituted C4-C12 bridged cycloalkyl,substituted or unsubstituted C6-C14 aromatic hydrocarbon, or asubstituted or unsubstituted C3-C10 monocyclic or polycyclic saturatedor unsaturated heterocyclic group containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur; X isCR³, wherein R³ is hydrogen, halogen, cyano, substituted orunsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl,substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstitutedC1-C6 alkoxy, substituted or unsubstituted amino, substituted orunsubstituted C6-C14 aromatic hydrocarbon, or a substituted orunsubstituted C3-C10 monocyclic or polycyclic unsaturated heterocyclicgroup containing 1 to 3 identical or different heteroatoms selected fromnitrogen, oxygen, and sulfur; and n is an integer of 0 to 3, whereinwhen n is 2 or 3, R¹ may be identical or different from each other. 2.The method according to claim 1, wherein in Formula (I), A is pyrazolylsubstituted with n-number of R¹; R¹ is halogen; cyano; C1-C6 alkyl thatmay be substituted with halogen or C1-C4 alkoxy; C3-C7 cycloalkyl;phenyl; or a C3-C6 monocyclic unsaturated heterocyclic group containingone oxygen atom or one sulfur atom; R² is linear C1-C6 alkyl or branchedC3-C8 alkyl that may be substituted with halogen, C3-C7 cycloalkyl thatmay be substituted with C1-C4 alkyl, phenyl, C1-C4 alkoxy, or one ormore C3-C6 monocyclic unsaturated heterocyclic groups containing oneoxygen atom or one sulfur atom; C3-C7 cycloalkyl that may be substitutedwith halogen, C1-C4 alkyl, halogeno C1-C4 alkyl, or C3-C5 cycloalkyl;C2-C6 alkenyl that may be substituted with halogen; or C4-C12 bridgedcycloalkyl that may be substituted with C1-C4 alkyl; X is CR³, whereinR³ is hydrogen; halogen; C1-C6 alkyl; C2-C4 alkynyl that may besubstituted with C1-C6 alkyl that may be substituted with hydroxy, C3-C7cycloalkyl that may be substituted with hydroxy, one or more C3-C6monocyclic saturated heterocyclic groups containing 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur, or oneor more C3-C10 monocyclic or polycyclic unsaturated heterocyclic groupsthat may be substituted with C1-C6 alkyl and contains 1 to 3 identicalor different heteroatoms selected from nitrogen, oxygen, and sulfur; orC1-C4 alkoxy that may be substituted with one or more C3-C6 monocyclicsaturated heterocyclic groups containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur; and n is aninteger of 1 or 2, wherein when n is 2, R¹ may be identical or differentfrom each other.
 3. The method according to claim 1, wherein thecompound represented by Formula (I) or a salt thereof is a compoundrepresented by Formula (II) below or a salt thereof:

wherein R¹ is halogen; cyano; C1-C6 alkyl that may be substituted withhalogen; C3-C7 cycloalkyl; phenyl; or a C3-C6 monocyclic unsaturatedheterocyclic group containing one oxygen atom or one sulfur atom; R² islinear C1-C6 alkyl or branched C3-C8 alkyl that may be substituted withhalogen, C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl,phenyl, C1-C4 alkoxy, or one or more C3-C6 monocyclic unsaturatedheterocyclic groups containing one oxygen atom or one sulfur atom; C3-C7cycloalkyl that may be substituted with halogen, C1-C4 alkyl, halogenoC1-C4 alkyl, or C3-C5 cycloalkyl; C2-C6 alkenyl that may be substitutedwith halogen; or C4-C12 bridged cycloalkyl; X is CR³, wherein R³ ishydrogen; halogen; C1-C4 alkyl; C2-C4 alkynyl that may be substitutedwith C1-C6 alkyl that may be substituted with hydroxy, C3-C7 cycloalkylthat may be substituted with hydroxy, one or more C3-C6 monocyclicsaturated heterocyclic groups containing 1 to 3 identical or differentheteroatoms selected from nitrogen, oxygen, and sulfur, or one or moreC3-C10 monocyclic or polycyclic unsaturated heterocyclic groups that maybe substituted with C1-C6 alkyl and contains 1 to 3 identical ordifferent heteroatoms selected from nitrogen, oxygen, and sulfur; orC1-C4 alkoxy; and n is an integer of 1 or 2, wherein when n is 2, R¹ maybe identical or different from each other.